Spiro(3alpha,5alpha - cyclo - 5alpha - androstane-7,1&#39;-cyclopropanes),their 3beta-hydroxy-delta5 and 3-keto-delta4-counterparts,and the 19-nor analogues of the foregoing

ABSTRACT

REPLACED BY M (X)   7-SPIROCYCLOPROPYL-,10-R1-ESTR-4-EN-3-ONE WHERE C17 IS   REPLACED BY M. (IX) AND 3-HO-,7-SPIROCYCLOPROPYL-,10-R1-ESTR-5(6)-ENE WHERE C17 IS   REPLACED BY M AND C3 AND C5 ARE CONNECTED BY ---.(VIII)   6-Z&#39;&#39;-O-,7-SPIROCYCLOPROPYL-,10-R1-ESTRANE WHERE C17 IS   THIS INVENTION RELATES TO NOVEL SPIRO(3A,5A-CYCLO-5AANDROSTANE-7,1&#39;&#39;-CYCLOPROPANES), THEIR 3B-HYDROXY-$5, AND 3-KETO-$4-COUNTERPARTS, AND THE 19-NOR ANALOGUES OF THE FOREGOING, EMBRACED BY THE FORMULAE:   WHEREIN $ IS A GENERIC EXPRESSION DENOTING A-AND BUONDS AND MIXTURES THEEOF; R1 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND METHYL; Z&#39;&#39; IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, ALKYL OF FROM ONE THROUGH TWELVE CARBON ATOMS, AND THE ACYL RADICAL OF A HYDROCARBON CARBOXYLIC ACID CONTAINING FROM ONE THROUGH TWELVE CARBON ATOMS; M IS SELECTED FROM THE GROUP CONSISTING OF (-CO-), (-C(-OZ)(-C*C-A)-) AND (-C(-OZ)(-R3)-) WHEREIN A IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, ALKYL OF FROM ONE THROUGH FOUR CARBON ATOMS, CHLORINE, BROMINE AND TRIFLUOROMETHYL, R3 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, ALKYL OF FROM ONE THROUGH TWELVE CARBON ATOMS AND ALKENYL OF FROM TWO THROUGH TWELVE CARBON ATOMS, AND Z IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND THE ACYL RADICAL OF A HYDROCARBON CARBOXYLIC ACID CONTAINING FROM ONE THROUGH TWELVE CARBON ATOMS. THE COMPOUND OF FORMULA VIII HAVE ANABOLIC, ANDROGENIC, ANTI-FERTILITY, CHOLESTEROL MOBILIZING, ERTHROPOIETIC, ESTROGENTIC AND ANTIHORMONAL ACTIVITIES. THE COMPOUNDS OF FORMULAE IX AND X HAVE CHOLESTEROL AND TRIGLYCERIDE SUPPRESSING, ESTROGENIC, ANTIESTROGENIC AND ERYTHROPOIETIC PROPERTIES. THE AFORESAID COMPOUNDS (VIII, IX AND X) ARE CONSEQUENTLY USEFUL IN TREATING MAMMALS, INCLUDING HUMANS, AND BIRDS IN THOSE CONDITIONS WHERE THE FOREGOING PROPERTIES MAKE THE NEW COMPOUNDS VALUABLE IN MEDICAL AND VETERINARY PRACTICE.

United States Patent Office 3,597,418 Patented Aug. 3, 1971i SPIRO[3a,5u CYCLO 5a ANDROSTANE ZY- CYCLOPROPANES], THEIR Erfi-HYDROXY-A AND S-KETO-N-COUN'IERPARTS, AND THE 19-NOR ANALOGUES OF THE FOREGOING J. Allan Campbell and John C. Babcock, Kalamazoo, Micllr, assignors to The Upjohn Company, Kalamazoo, Mic No Drawing. Filed July 29, 1969, Ser. No. 845,891

lint. Cl. C07c 173/10 US. Cl. 260-2395 13 Claims ABSTRACT OF THE DISCLOSURE This invention relates to novel Spil[3a,5oc-CyC105aandrostane-7,l-cyclopropanes], their 3 3-hydroxy-A and 3-keto-A -counterparts, and the l9-nor analogues of the foregoing, embraced by the formulae:

til

wherein f is a generic expression denoting 05- and a -bonds and mixtures thereof; R is selected from the group consisting of hydrogen and methyl; Z is selected from the group consisting of hydrogen, alkyl of from one through twelve carbon atoms, and the acyl radical of a hydrocarbon carboxylic acid containing from one through twelve carbon atoms; M is selected from the group consisting of (III) ?Z OZ o (resort) r-R3) wherein A is selected from the group consisting of hydrogen, alkyl of from one through four carbon atoms, chlorine, bromine and trifiuoromethyl, R is selected from the group consisting of hydrogen, alkyl of from one through twelve carbon atoms and alkenyl of from two through twelve carbon atoms, and Z is selected from the group consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic acid containing from one through twelve carbon atoms. The compounds of Formula VIII have anabolic, androgenic, anti-fertility, cholesterol mobilizing, erthropoietic, estrogenic and antihormonal activities. The compounds of Formulae [IX and X have cholesterol and triglyceride suppressing, estrogenic, antiestrogenic and erythropoietic properties. The aforesaid compounds (VIIII, IX and X) are consequently useful in BRIEF SUMMARY OF THE INVENTION The novel compounds of this invention, intermediates therefor and process for their production are illustratively represented by the following sequence of formulae:

CH3 CH3 0 0 I R1 R] p HO Rgozso I II CH; on, l M R1 I RI E- III I1 I 0 IV 0H III 0H, CH; (\/M R:

CH l/ R1 I l 1 oz VIII i) VII l (+VIIa and VIIb) CH3 CH fi/ (\l R R1 R1 HO 1 HO 6 IX 1'1 XII wherein f, R Z and M have the same meaning as above; R is an organic radical selected from the group consisting of alkyl of from one through twelve carbon atoms and aryl of from six through twelve carbon atoms; the symbol attached to the 7-position of the steriod nucleus represents a 7,l-spirocyclopropyl radical of the formula CH l... which substituent will henceforth be designated 7-spirocyclopropy In this application the term acyl means the acyl radical of an organic carboxylic acid, preferably a hydrocarbon canboxylic acid of from one through twelve carbon atoms, for example, saturated and unsaturated aliphatic acids and aromatic acids, such as acetic, propionic, butyric, valeric, caproic, caprylic, octanoic, decanoic, dodecanoic, tripropylacetic, crotonic, cyclopentylacetic, cyclopentylpropionic, cyclohexylacetic, benzoic, toluic, ethylbenzoic, phenylbutyric, phenylvaleric, cinnamic, naphthaleneacetic, p-butoxyphenylpropionic, phenylpropiolic, glutaric, maleic acids, and the like. The term alkyl means an alkyl radical, preferably of from one through twelve carbon atoms, such as methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and isomeric forms thereof. The term alkenyP means an alkenyl radical, preferably of from two through twelve carbon atoms, for example, ethnyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl and isomeric forms thereof. The term alkynyl means an alkynyl radical, preferably of from two through five carbon atoms, for example, ethynyl, propynyl, butynyl, pentynyl and isomeric forms thereof. The term haloalkyny means a haloalkynyl radical, preferably of from two through five carbon atoms; it differs from an alkynyl radical by having one or more of its hydrogen atoms substituted by halogen; typical haloalkynyl radicals are chlorethynyl, bromoethynyl, trifluoromethylethynyl, and the like. The term ary means an aryl radical of from six through twelve carbon atoms, such as phenyl, tolyl, xylyl, naphthyl, alkylnaphthyl, diphenyl, and the like.

The novel compounds embraced by Formulae VI through XIV of the flow-sheet, above, are prepared by the route shown therein, employing the methods and reactions described below.

The novel compounds of Formula VI through XIV are prepared from the known starting materials of Formula I of the flow-sheet. The compounds of Formula I are known in the art and may also be synthesized in the manner 4 described in US. Patent 3,3 80,886, wherein the procedures for obtaining the corresponding 7-methy1 compounds are set forth.

(1) The first step of the novel process involves the 3- sulfonylation of the compounds of Formula I, e.g., by

mixing them with an excess of an organic s-ulfouyl halide (in pyridine) to yield the 3-aryl or 3-alkyl sulfonate of a 3fl-hydroxy-5-androstene-17-one (II).

(2) The next step of the process comprises subjecting the compounds of Formula II to the i-steroid rearrangement (see: Fieser and Fieser, Steroids, pages 314 through 316, Reinhold Publishing Corp., New York, N.Y., 1959) to give the compounds of Formula III. By this procedure a 3-aryl or alkyl sulfonate of the compounds of Formula II, on heating at reflux in an inert solvent such as acetone or benzene containing water, with an alkali metal acylate, e.g., potassium acetate, sodium benzoate, potassium phenylacetate, etc., yields the corresponding 6fi-hydroxy- Mia-cycloandrostane17-ones of Formula III.

(3) A 17-keto compound of Formula III is converted to a corresponding 65,17/3-dihydroxy compound (III') by the known methods described in (a), b), (c), (d), (e) and (f), below.

(a) By reducing the 6/3-ol-17-one compounds of Formula III exclusively at the l7-position, e.g., by reaction with sodium borohydride, lithium tri-t-butoxy aluminium hydride, lithium aluminum hydride and the like, to give the corresponding l7uH-3a,5a-cycloandrostane-6p,17,8- diols (111').

(b) By mixing the 17-ketones (III) with an alkyl lithium (e.g., methyl lithium, ethyl lithium, propyl lithium, butyl lithium, etc.) to yield the corresponding 17-alkyl- 3a,5a-cycloandrostane-6/3,l7fl-diols (III'). The reaction is advantageously conducted in excess of the stoichiometric proportion, preferably in an amount of at least 1.5 moles of alkyl lithium per mole of starting 17-ketone (III).

(0) By mixing the 17-ketones of Formula III with an appropriate Grignard reagent, i.e., an alkyl magnesium halide or an alkenyl magnesium halide such as methylmagnesium bromide, ethylmagnesium chloride, propylmagnesium iodide, hexylmagnesium bromide, alkylmagnesium chloride, 3-pentenylmagnesium bromide, 4-nonenylmagnesium iodide, etc., in the presence of a solvent such as ether, tetrahydrofuran, benzene and the like, to produce the corresponding 17a-alkyl (or L-21lk61'1Yl)-30t,50ccycloandrostane-6B,17/3-diols (III'). Preferably the Grignard reagent is employed in an excess of the order of 3 to 10 moles per mole of starting l7-ketone (III).

((1) By mixing the 17-ketones (III) with an alkali metal derivative such as lithium acetylide, sodium acetylide, potassium acetylide, sodium or potassium methylacetylide, sodium or potassium ethylacetylide, sodium or potassium propylacetylide, sodium butylacetylide, etc., in the presence of an inert solvent such as dioxane, dimethylformamide or dimethylsulfoxide, to yield the corresponding 17oz alkynyl 301,50: cycloandrostane 6fl,17,8 diols (III').

(e) By treating the l7-ketone (III) with an alkynylmagnesium halide (prepared by slowly passing a gas such as acetylene, methylacetylene, propylaceaylene, butylacetylene, etc., through an ether solution of an alkylmagnesium halide, such as methylmagnesium bromide) in a solvent, such as tetrahydrofuran, ether, benzene, etc., to yield the corresponding 17a-alkynyl-3c it-cycloandrostane6;3,17,8-diols (111).

(f) The 17a alkynyl 30,5oc cycloandrostane 6,6, l7fi-diols (III), prepared as in (d) and (e), above, are hydrogenated, e.g., in the presence of a suitable hydrogenation catalyst (such as palladium on charcoal) to obtain the corresponding 17a-alkenyl (or alkyl)-3a,5or-cycloandro- Stan-66,17fl-diols (111'). When the Not-alkynyl compounds (III) are reduced with 1 molar equivalent of hydrogen, the corresponding 17a-alkenyl products (111') are obtained; using 2 molar equivalents yields the 17a-a1kyl coun terparts (III).

(4) The 6B-hydroxy-17-keto compounds of Formula III and the 6,8,17fi-diols of Formula III are oxidized exclusively at the 6-position to yield the corresponding 6,17 diketones (IV) and 6-keto-17,B-ols (IV), respectively, by the known procedures set forth in (a), (b), and (c), below.

(a) By mixing the 3a,5a-cycloandrostane-6fi-ol-17-ones (III) with chromium trioxide-pyridine complex at moderate (room) temperature, in accordance with the procedure described in Tetrahedron 24, 4037, to yield the corresponding 3a,5ot-cycloandrostane-6,17-diones (IV). AI- ternatively, instead of using the chromium trioxide-pyridine complex as the oxidant, Jones reagent (8 N chromium trioxide in concentrated sulfuric acid diluted with water) on mixing with the 6[3-01170nes (III) dissolved in acetone, also yields the corresponding 6,17-diones (IV).

(b) By mixing the 17aH-3or,5a-cycloandrostane-6fi,17B- diols (III) with manganese dioxide (in accordance with the procedure of Example 1 of US. Patent 2,842,542) to give the corresponding 17aH-17,8hydroxy-3or,5or-cycloandrostan-G-ones. (IV). Another (and preferable) procedure is available, namely, first mixing the l7otH-3oc,5otcycloandrostane-6B,17,8-diols (III) (in pyridine) with an acid anhydride of a hydrocarbon carboxylic acid to give the corresponding 6fi,17,8-diacylates (III'), and then producing the corresponding 17uI-I-l7fi-hydroxy-3a,5a-cycloandrostane-6-one 17-acylates (IV) by following the alternative oxidation procedure described at the end of (a), above.

(c) By following the oxidation procedure of (a), above, the 17m alkyl-3or,5a-cycloandrostane 65,173- diols (III) the 17a-alkynyl-3a,5or-cycloandrostane-6fi,17,8- diols (III) and the l7or-alkenyl-3or,5rr-cycloandrostane- 6,8,17B-diols (III) yield, respectively, the corresponding 17u-alkyl-17B-hydroxy-3 a,5 a-cycloandrostan-fi-one (IV), the 17a-alkynyl-17fl-hydroxy-3a,5a-cycloandrostane-6-one (IV) and the 17a-alkenyl-17fi-hydroxy-3or,5a-cycloandrostane-6-one (IV). The thus produced l7B-ols (IV) are converted to their corresponding 17-acylates by known procedures, e.g., by mixing (in pyridine) with an anhydride or halide of an organic carboxylic acid at moderate (room temperature (l7aH) and by heating in an anhydride or an anhydridepyridine mixture at elevated temperatures (17or-alkyl, alkenyl and alkynyl).

(5) In this step of the process, the 6-keto-compounds of Formula IV are converted to their 7-methylene counterparts (V) by heating, preferably at reflux, with paraformaldehyde in the presence of an acid salt (e.g., a dialkylammonium halide) in a solvent such as dioxane.

(6) In this step, the 7-methylene compounds of Formula V on mixing with diazomethane at low (room) temperature yield the corresponding spiro[7,3 [1] pyrazolines] (VI).

(7) Heating the spiro[7,3' [1]pyrazolines] of Formula VI produced in the previous step (e.g., under vacuum and at about 150 C.) gives, respectively, the corresponding 7-spirocyclopropyl-3a,5or-cycloandrostan-6-ones (VII), the 7-ethylidene-3a,5a-cycloandrostan-6-ones (VIIa) and the 7 (2-hydroxyethyl -3 oc,5 a-cycloandrostan-6-ones (VIIb The compounds of Formula VII wherein M is are converted to the corresponding 17,8-ol-6-ones (VII) by reduction at the 17-position, e.g., by mixing with lithium aluminum tri-t-butoxyhydride, sodium borohydride and like reducing agents. Compounds of Formula VIIb are useful as chemical intermediates since they can be converted to the corresponding 2-tosylate and, on treatment with base, provide additional amounts of the 7-cyclopropyl steroid (VII).

(8) In this step of the process, the 7-spirocyclopropyl- 3u,5vr-cycloandrostan-6-ones (VII) are reduced (e.g.,

with sodium borohydride) at the 6-position to give the corresponding 6oc-O1S (VIII). When X is it will be reduced so that M will become The acylation of the compounds of Formula VIII wherein Z is hydrogen is carried out in the usual manner, i.e., by mixing with an acid anhydride or acid halide of an organic car boxylic acid in pyridine at room temperature for several days. When M is the 17,8-hydroxyl group is also acylated and the 6,17- diacylates (VIII) are produced.

The 17-monoacylates of Formula VIII wherein M is wherein Z is lower acyl and R is hydrogen are produced by sodium borohydride reduction of the corresponding compound of Formula VII wherein M, Z and R are defined as above. The 6-monoacylates of Formula VIII wherein M is oz C----Ra and Z and R are hydrogen are ordinarily prepared from the 6,17-diacylates of Formula VIII wherein Z and Z are acyl, by selective hydrolysis of the 17-acyl function Z, preferably using an alkali metal bicarbonate in water and an alkanol such as methanol at room temperature for several hours. Said selective hydrolysis is most conveniently performed on compounds of Formula VIII where in Z is the acyl radical of a hydrocarbon carboxylic acid of from two through twelve carbon atoms and Z is formyl or trifluoroacetyl, although when desired Z and Z can be the same.

The 6-keto compounds of Formula VII wherein M is are converted to their 6a-ol counterparts (VIII), i.e., the 7-spirocyclopropyl-6a-hydroxy 304,50: cycloandrostan- 17-ones (VIII) by the known procedures of J. Amer. Chem. Soc. 76 5024, employed in the manner recited in (a), (b) and (0), below.

(a) By heating the 7-spirocyclopropyl-3u,5or cycloandrostane-6,17-diones (VII) in 2-methyl-2-ethyl1,3- dioxolane in the presence of a ketalization catalyst such as p-toluenesulfonic acid, to yield the corresponding 7- spirocyclopropyl 30,5a cycloandrostane-6,17-dione 17- ketals.

(b) By mixing the thus produced 7-spirocyclopropyl- 3or,5a-cycloandrostane-6,17-dione 17-ketals with a reducing agent such as sodium borohydride at low temperature, to yield the corresponding 7-spirocyclopropyl6ahydroxy-3u,5a-cycloandrostan-l7-one 17-ketals.

(c) By mixing the 17-ketal compounds produced in (b), above, in a solvent such as acetone in the presence of a catalyst such as p-toluenesulfonic acid at moderate (room) temperature to give the corresponding 7-spirocyc1opropyl-6ot-hydroxy-3u,5vt-cycloandrostan 17 ones (VIII). The 6-acylation of the thus produced compounds of Formula VIII wherein Z is hydrogen is carried out in the usual manner, namely, by mixing with an acid anhydride or acid halide of an organic carboxylic acid in pyridine at room temperature for several days.

The 6OL-O1-17-k6t0 compounds of Formula VIII are converted to their 60,17fi-diOl-l7oc-hYdf0g6I1 (and 17aalkyl, 17u-alkynyl and 17a-alkenyl) counterparts (VIII) in accordance with the procedures of section (3), above.

(9) In the next step of the process, the compounds of Formula VIII are readily rearranged, for example, by mix-ing with a strong acid, e.g., hydrochloric acid, at low temperature, to give the corresponding 7-spirocyclopropyl-5-androsten-3fi-ols (IX).

The thus produced compounds of Formula IX are mixed with an organic sulfonyl halide in a base such as pyridine to yield the corresponding 7-spirocyclopropyl- 5-androsten-3B-ol 3-aryl (or alkyl) sulfonates. Excess sulfonyl halide is employed except when M is wherein R and Z are hydrogen; -in this instance, 1 to 1.2 equivalents of sulfonyl halide is used for each equivalent of the compounds of Formula IX.

Subjecting the thus produced 5-androsten-3fi-ol 3-aryl (or alkyl) sulfonates to the i-steroid rearrangement, in the manner described in (2), above, yields the corresponding 7 spirocyclopropyl 300,50: cycloandrostan-6fi-ols (VIII). When this procedure is modified by omitting an inert solvent (such as acetone, benzene, etc.) and substituting therefor an alkanol (such as methanol, ethanol, propanol, etc.), there are produced the corresponding 3o,5a-cycloandrostan-6fi-alkoxy compounds of Formula VIII.

The 6B-ols (VIII) are converted to the corresponding 6,8,l7B-diol 6,17-diacylates (VIII) and 6,8,17B-dil 6- monoacylates (VIII) in the same manner as shown for their 606-01 counterparts (VIII) in (8), above.

(10) The 7-spirocyclopropyl-5-androsten-3,B-ols (IX), prepared in (9), above, are preferentially oxidized at the 3-position by the Oppenauer method, in the manner described in J. Amer. Chem. Soc. 76, 5674, e.g., in a cyclohexanone and toluene solution, employing aluminum isopropoxide as catalyst, at reflux temperature, to yield the corresponding 7-spirocyclopropyl-4-androsten- 3-ones (X).

(11) The thus produced compounds of Formula X, are converted to the corresponding 7-spirocyclopropyl 17B-hydroxy-5B-androstan-3-ones (XI) by hydrogenation of the A -bond. For example, mixing the aforesaid 3- keto-M-compounds of Formula X in a solvent such as 95% ethyl alcohol, at room temperature, in the presence of a hydrogenation catalyst such as palladium on carbon, with hydrogen until one mole equivalent is consumed, yields the corresponding 3-keto-5B-androstanes (XI).

(12) The 7-spirocyclopropyl-S-androsten-Iifl-ols (IX) prepared in (9), above, are hydrogenated at the 5-position by known procedures, e.g., by mixing with hydrogen (at atmospheric pressure) in the presence of a catalyst such as platinum dioxide, to yield the corresponding 7- spirocyclopropyl-5wandrostan-3B-ols (XII).

(13) The 7-spirocyclopropyl-4-androsten-3-ones (X) prepared in above, on treating with liquid ammonia and lithium in an alkanol, give the corresponding 7-spirocyclopropyl-Sa-androstan-3 (0c and fi)-ols (XII). However, the compounds of Formula X, on treating with liquid ammonia and lithium in a solvent such as tetrahydrofuran, yield corresponding 7-spirocyclopropyl-5aandrostan-3-ones (XIII). The thus produced compounds of Formula XIII are reduced in known manner at the 3- position, e.g., with sodium borohydide, to yield the corresponding 7-spirocyclopropyl-5a-androstane-3 (a and fi)-diols (XII). The compounds of Formula XH can be oxidized in known manner at the 3-position, e.g., with chromium trioxide, to yield the corresponding 7-spirocyclopropyl-S m-androstan-3 -ones (XIII) (14) The 7-spirocyclopropyl-5,B-androstan-3-ones (XI) prepared in (11), above, are reduced in known manner 8 at the 3-position, e.g., with sodium borohydride, to yield the corresponding 7-spirocyclopropy1-5fi-androstan-3 (oz and B)-ols (XIV).

The 3,17-diketo compounds of Formulae X, XI and XIII are converted to their corresponding l7a-alkyl, alkynyl, haloalkynyl, and alkenyl, derivatives essentially as described in the procedures of (3), above, but with an important variation. The aforesaid 3,17-diketones, prior to the formation of the above enumerated 17oc-Sllbstituents, must first be converted to the corresponding 3-enamines, 3-ketals or 3-enol ethers in order to protect the 3-keto function from reduction. The 3-enamine formation can be carried out in the manner described in US. Pat. 2,781,343, namely, by reaction with a secondary cyclic alkyleneamine containing from five through seven ring atoms, such as pyrrolidine, piperidine, morpholine and their C-alkyl substituted derivatives such as 2,4-dimethylpyrrolidine, 3-propylpiperidine, 3-methylmorpho line, etc. Pyrrolidine is the preferred amine for use in this reaction.

Advantageously, the 3-enamines are prepared by heating one of the desired aforesaid 3,17-diketones and one of the appropriate secondary cyclic alkyleneamines together in the presence of a suitable solvent, for example, a lower alkanol such as methanol, ethanol, etc. The desired 3-enamines generally separate from their reaction mixtures and are isolated and dried. They are used, without further purification, in the next stage of the synthesis, which is identical to the procedures outlined in (b) through (f) of (3), above, to yield, after routine hydrolysis of the enamine, the corresponding l7a-alkyl, 17aalkynyl, 17whaloalkynyl and 17a-alkenyl-3-ketones of Formulae X, XI and XIII.

All of the compounds included within Formulae I through XIV of the flow-sheet, above, can be isolated from their respective reaction mixtures by conventional means, for example, when a water-miscible solvent is used, by pouring the reaction mixture into water and separating the resulting precipitate by filtration or by extraction with water-immiscible solvents. Additional purification of the products can be accomplished by conventional means, for example, by elution chromatography from an adsorbent column with a suitable solvent such as acetone, ethyl acetate, ether, methylene chloride and Skellysolve B (hexanes), mixtures and combinations of these solvents; also by gradient elution chromatography from an adsorbent column with a suitable mixture of solvents, such as, methylene chloride-Skellysolve B, acetone-Skellysolve B, and the like.

The compounds embraced by Formulae VIII through XIV possess the pharmacological activities recited above for those of Formulae VIII, IX and X, and are consequently useful in treating humans, mammals, birds and other animals in those conditions and/or ailments where such activities are desired. For example, in treating and preventing atherosclerosis, preventing pregnancy, increasing pelt size and quality in female mink, in treating osteoporosis, erythropenia, etc.

The compounds of Formulae VI and VII are useful as intermediates in preparing the pharmacologically active products of Formulae VIII through XIV.

The compounds of Formulae VIII through XIV of the invention can be prepared and administered to humans, mammals, birds and animals, in a wide variety of oral or parenteral dosage forms, singly or in admixture with other coacting compounds, in doses of about 1 to 1,000 mg. one to three times a day, depending on the severity of the condition being treated and the recipients response to the medication. They can be administered with a pharmaceutical carrier which can be a solid material or a liquid in which the compound is dissolved, dispersed or suspended. The solid compositions can take the form of tablets, powders, capsules, pills, or the like, preferably in unit dosage forms for simple administration or precise dosages. The liquid compositions can take the 9 form of solutions, emulsions, suspensions, syrups or elixirs.

DETAILED DESCRIPTION The following preparations and examples describe the manner and process of making and using the invention and set forth the best mode contemplated by the inventors of carrying out their invention, but are not to be construed as limiting the scope thereof.

PREPARATION 1 l 9-n0r-3,5 -andrstadiene-3 ,1 7 fi-diol 3,1 7-diace-tate (b) A solution comprising 1 g. of 19-nor-17fi-hydroxy-4- androsten-3-one (a) (also known as l9-nortestosterone or l7B-hydroxy-4-estren-3-one, and prepared as in J. Amer. Chem. Soc. 75, 5366), 40 mg. of paratoluenesulfonic acid, and 8 ml. of acetic anhydride in 2 0 ml. of toluene is refluxed under nitrogen for about hours. Most of the solvent is removed with a stream of nitrogen to give a precipitate. A few milliliters of methanol containing a few drops of pyridine is added to the precipitate to yield crystals which are filtered, washed with cold methanol and dried to yield the desired product. This material is recrystallized by dissolving it in methylene chloride and diluting with methanol at room temperature to give pure 19-nor-3,5-androstadiene-3,l7fi-diol 3,17-diacetate (b).

PREPARATION 2 19-n0r-5-androstene-3/i,17B-di0l 17-acetate (c) To a solution of 0.5 g. of 19-nor-3,S-androstadiene- 3,17,B-diol 3,17-diacetate (b) (obtained in Preparation 1) in 15 ml. of 95% ethanol purged with nitrogen, a solution of 0.5 g. of sodium borohydride dissolved in 15 ml. of 95% alcohol (also purged of nitrogen) is added. The resulting solution is kept at room temperature for about 18 hours and then concentrated to a volume of about 20 ml. Dilute acetic acid (purged with nitrogen) is added. The product is extracted with ether, Washed with dilute acid, water, dilute sodium hydroxide solution, again with Water until the washings are neutral, dried over sodium sulfate and concentrated to dryness. Crystallization from acetone and Skellysolve B yields pure 19-nor-5-androstene- 3,8,17,8-diol 17-acetate (c).

PREPARATION 3 l9-n0r-5-andr0stene-3p,17,8-di0l 3 -tetrahyd r0pyranyl ether 17-acetate (d) To 1.8 g. of 19-nor-5-androstene-3fi,17fl-diol 17-acetate (c) (obtained as in Preparation 2) suspended in 10 ml. of dihydropyran and 50 m1. of ether, 100 mg. of paratoluenesulfonic acid is added. The ether solution is stored for about 16 hours, extracted with sodium bicarbonate solution, saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to yield 19-nor-5-androstene-3/i,17;?- diol 3-tetrahydropyranyl ether 17-acetate (d).

PREPARATION 4 19-nor-5-androstene-3BJ 7fl-di0l 3-tetrahydr0pyranyl ether (e) The residue of 19-n0r-5-androstene-3 3,17/8-diol 3-tetrahydropyranyl ether (d) (obtained in Preparation 3) is dissolved in 100 ml. of 5% potassium carbonate in methanol water (4:1) solution and the reaction mixture heated to reflux for about 1.5 hours. The solvents are evaporated under reduced pressure to give a residue of 19 nor 5 androstene 318,175 diol 3 tetrahydropyranyl ether (e).

PREPARATION 5 19-n0r-3fi-hyar0xy-5-andr0sten-17-0ne 3-tetrahydr0- pyanyl ether (f) The residue of 19-nor-5-androstene-3fi,17,8-diol 3-tetrahydropyranyl ether (e) (obtained in Preparation 4) is taken up in 10 ml. of pyridine and added to pyridinechromic acid complex prepared from 2 g. of chromic anhydride in 20 ml. of pyridine. The reaction mixture is stirred for about 16 hours at room temperature, diluted with a 1:1 mixture of ether and benzene and filtered on a Celite (diatomaceous earth) pad. The filtrate is washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure, and the residual pyridine distilled azeotropically with toluene under reduced pressure to yield a residue of l9-nor-3B-hydroxy- 5-androsten-17-one 3-tetrahydropyranyl ether (f).

PREPARATION 6 19-11or-fifl-hydroxy-S-androsren-I7-0ne (I) The residue of 19-nor-3fi-hydroxy-S-androsten-17-one 3-tetrahydropyranyl ether (f) (obtained in Preparation 5) is taken up in 20 ml. of acetone and 2 ml. of 3 N hydrochloric acid added thereto. The reaction mixture, after standing at room temperature for about 16 hours, is diluted with water and extracted with methylene chloride. The methylene chloride extract is Washed with water, dried over sodium sulfate and the solvent evaporated under vacuum. The residue is purified by chromatography and recrystallized from acetone-Skellysolve B (hexanes) to give 19-nor-3,13-hydroxy-5-androsten-l7-one (I).

PREPARATION 7 1 9-n0r-3 fi-hydroxy-S -andr0sten-1 7-0ne 3-p-t0luenesulfonate (II A solution of 0.1 g. of 19-nor-3,8-hydroxy-5-androsten- 17-one (I) (obtained in Preparation 6) and 0.1 g. of p-toluenesulfonyl chloride in 1 ml. of pyridine is kept at room temperature for about 48 hours. An additional 50 mg. of p-toluenesulfonyl chloride is added to the reaction mixture and after about 4 hours water is added to precipitate the product. The product is collected, washed with water, dried and recrystallized from a mixture of acetone and Skellysolve B (hexanes) to yield 19-nor-3B- hydroxy-S-androsten-17-one 3-p-toluenesulfonate (II).

PREPARATION 8 3B-hydr0xy-5-andfosten-17-0ne 3-p-t0luenesulf0nate (11) Following the procedure of Preparation 7 but substituting SB-hydroxy-S-androsten-l7-one (I) (prepared as in J. Amer. Chem. Soc. 57, 1379) as starting material, yields 3fi-hydroxy-5-androsten47-one 3-p-toluenesulfonate (II).

PREPARATION 9 6 B-hydroxy-l 9-n0r-3 (1,5 ot-cycloandrostan-l 7-one (III A solution of 0.3 g. of potassium acetate in 7 ml. of Water and 7 m1. of acetone is purged with nitrogen and 0.1 g. of 19-nor-3,8-hydr0xy-5-androsten-17-one 3-p-toluenesulfonate (II) (obtained in Preparation 7) added. The mixture is heated at reflux temperature for about 6 hours and the acetone evaporated with a fast stream of nitrogen. The crude product (III) is chromatographed through a silica gel (silicic acid) column and recrystallized from aectone-Skellysolve B (hexanes) to give 6B-hydr0xy-19- nor-3u,5a-cycloandrostan-l7-one (III).

PREPARATION 10 6,8-hydroxy-3u,5ot-cycloandr0st an-17-0ne (III) Following the procedure of Preparation 9 but substituting 3B hydroxy 5 androsten 17 one 3 p toluenesulfonate (II) (obtained in Preparation 8) as starting material, yields 6,8-hydroxy-3a,5a-cycloandrostan-17-one (III).

PREPARATION 11 To a solution of 0.25 g. of 6B-hydroxy-19-nor-3a,5ucycl0androstan-17-one (III) (obtained in Preparation 9) 1 1 in 10 ml. of methanol, 0.07 g. of sodium borohydride is added with cooling in an ice bath. After about /2 hour, water is added and the precipitated product is collected. The product is recrystallized twice from a mixture of acetone aud Skellysolve B to give 19-nor-3a,5a-cycloandrostane-6fl,17fi-diol (III).

PREPARATION 12 3a,5ot-cycl0andr0stane-6,B,17p-di0l (111) Following the procedure of Preparation 11 but substituting 6fi-hydroxy-3a,5a-cycloandrostan-17-one (III) (obtained in Preparation 8) as starting material, yields 3 a,5a-cyclonandrostane-6{3, 175-diol (III' PREPARATION 13 A solution of 0.1 g. of 19-nor-3u,5a-cyclonandrostane- 6/3-hydroxy-17-one (III) (obtained in Preparation 9) in 5 ml. of 2 N methylmagnesium bromide in a mixture of equal parts of benzene and tetrahydrofuran, is heated under reflux for about 18 hours. Most of the solvent is evaporated with a stream of nitrogen. The concentrated material remaining is poured into ice-water, acidified with dilute hydrochloric acid and extracted with ether. The extract is washed with sodium bicarbonate solution, water, dried, and the solvent removed. It is chromatographed through a column of neutral alumina. Unreacted starting material (III) is eluted first. The desired product is then eluted and crystallized from aqueous acetone to give 17:! methyl 19 nor 3a,5a cycloandrostane- 65,176-diol (III). 1

Following the procedure of Preparation 13 but substituting for methylmagnesium bromide, other Grignard reagents, such as (1) ethylmagnesium chloride,

(2) isopropylmagnesium bromide, (3) pentylmagnesium chloride,

(4) octylmagnesiurn bromide,

(5) undecylmagnesium chloride, etc.,

yields respectively,

(1) 17u-ethyl-19-nor-3 u,5a-cycloandrostane-6B,17p-

diol (III),

(2) Not-isopropyl-19-nor-3a,5a-cycloandrostane-6/3,17/3- diol (III),

(3 17a-pentyl-19-nor-3a,5u-cycloandrotane-6fi,17,8-

diol (III),

( 4) 17a-octy1-19-nor-3 a,5a-cycloandrostane-6p,17B-diol (5) 17a-undecyl-19-nor-3 a,5a-cyc1oandrostane-6/3, 17$- diol (III), etc.

PREPARATION 14 1 7 ot-methyl-3u,5 a-cyclandr0stane-6BJ 7 {B-diol (111') Following the procedure of Preparation 13 but substituting 63 hydroxy 30,5a cycloandrostan 17 one (III) (obtained in Preparation 10) as starting material, yields 17oz methyl 311,50: cyclonandrostane 65,1718- diol (111').

Following the procedure of Preparation 13 but substituting for methylmagnesium bromide, other Grignard reagents, such as (1 sec. butylmagnesium bromide, (2) heptylmagnesium chloride,

(3) nonylmagnesium bromide,

(4) decylmagnesium chloride,

() dodecylmagnesium bromide, etc.,

yields, respectively,

(1) 17a-S6C. butyl-3 u,5u-cycloandrostane-6;8,17,8-d1o1 (2) 17u-heptyl-3a,5a-cycloandrostane-6fi,l7,6-diol (III),

(3) l7u-nonyl-3a,5a-cycloandrostane-6fi,17(3-dio1 (III),

12 (4) 17a-decyl-3a,5a-cycloandrostane-6/3,17fi-diol (III), (5) 17a-dodecyl-3 a,5a-cyc1oandrostane-6B,17,8-diol (III), etc.

PREPARATION 15 A suspension of sodium acetylide (20% in xylene) is centrifuged and the sludge slurried with 10 ml. of dimethylsulfoxide. A mixture of 0.1 g. of 6fi-hydroxy-19-nor- 3u,5a-cycloandrostan-17-one (III) (obtained in Preparation 9) in 5 ml. of dimethylsulfoxide is mixed with the sodium acetylide. After keeping the mixture at room temperature for about a half hour it is stored in the refrigerator for about 16 hours. Water is added to the frozen mixture and the product extracted with ether. The ex? tracts are washed successively with dilute acid, sodium bicarbonate solution, and water, and the solvent then removed to give an oily residue. The residue is chromatographed through neutral alumina; recrystallization of the crude product gives pure 17a-ethynyl-19-nor-3u,5a-cycloandrostane-6,8, 17,8-diol (III) Following the procedure of Preparation 15 but substituting for sodium acetylide, other alkynylating agents, such as yields, respectively,

sodium methylacetylide,

sodium trifiuoromethylacetylide, sodium propylacetylide,

lithium acetylide,

sodium butylacetylide, etc.,

(1 17a l-propynyl) -l9-nor-3a,5a-cycloandrostane- 6,8,17B-diol (III),

(2) 17a-trifluoromethylethynyl-19-nor-3major-cycloandrostane-6B,17B-diol (III),

(3) 17a(l-pentynyl)-19-nor-3u,5a-cycloandrostane- 6,8,17fi-dio1 (III),

(4) 17et-ethynyl-l9-nor-3a,5a-cycloandrostane-6fl,17/3- diol (III),

(5) l7a(1-hexynyl)-19-nor-3a,5a-cycloandrostane-6fl,

17fi-diol (III), etc.

PREPARATION 16 1 7 a-ethynyl-3a,5 a-cycl0andr0stane-613J 7 p-diol (111) Following the procedure of Preparation 15 but substituting 613-hydroxy 3a,5a cycloandrostan-l7-one (III) (obtained in Preparation 10) as starting material, yields 17u-ethynyl-3u,5u-cycloandrostane-6p,175-dio1 (111').

Following the procedure of Preparation 16 but substituting for sodium acetylide, other alkynylating agents, such as (1) sodium ethylacetylide,

(2) sodium propylacetylide,

(3) sodium bromoacetylide,

(4) sodium chloroacetylide,

(5) sodium trifiuoromethylacetylide, etc.,

yields, respectively,

PREPARATION 17 1 7ot-vinyl-1 9-n0r-3 01,5 a-cycloand rowan- 6 8,1 7 p-d iol (III A catalyst comprising a suspension of mg. of 1% palladium on charcoal in 30 m1. of dioxane (purified by passage through a column of alumina) is reduced at atmospheric pressure With hydrogen. A solution of 0.4 g. of 170: ethynyl-19-nor-3 a,5a-cycloandrostane-6/8,l7B-diol (III') (obtained as in Preparation 15) in ml. of dioxane is injected through a rubber stopper into the reaction flask containing the catalyst. Hydrogenation is continued until 1 mole (3325 ml.) of hydrogen is consumed at at mospheric pressure. The catalyst is removed by filtration and the filtrate concentrated to dryness on a rotary evaporator. The residue is chromatographed through a column of 125 g. of Florisil (synthetic magnesium silicate). The eluted material is recrystallized from aqueous methanol. Recrystallization from the same solvent gives l7oc-vinyl- 19-nor-3a,5a-cycloandrostan-6B,17,8-diol (III).

Following the procedure of Preparation 17 but substituting other 17a-alkynyl compounds as starting materials, such as (1) 17a (-l-propynyl) -19-nor-3 01,5 a-cycloandrostane- 613,17/3-diol (III (2) 17u-trifluoromethylethynyl- 19-n0r-3 a,5a-cyclo androstane-6,8,17B-diol (III') etc.,

yields, respectively,

PREPARATION 18 1 7oc-vinyl-3 oc,5 ot-cycloandrostan-o 5,1 7,8-di0l (111') Following the procedure of Preparation 17 but substituting 17a-ethynyl 311,504 cycloandrostane-6fl,17fi-diol (III') (obtained in Preparation 16) as starting material, yields 17e-vinyl-3a,5a-cycloandrostan-6fi,l7fi diol (III').

Following the procedure of Preparation 18 but substituting the other l7a-alkynyl compounds as starting materials, such as (1) l7a( l-butynyl -3a,-5o-cycloandrostane-65,17fi-diol (2) 17a(1-pentynyl)-3a,5 a-cycloandrostane-6p,17B-diol (III'), etc.,

yields, respectively,

PREPARATION 19 19-n0r-3a,5a-cycl0andr0stane-6/3J 7 B-diol 6,17-a'iacetate III A solution of 1 g. of 19-nor-3a,5a-cycloandrostane- 63,17/3-diol (III') (obtained in Preparation 11) in 1 ml. of pyridine and 1 ml. of acetic anhydride is kept at room temperature for about 16 hours. Ice and water are added and the product extracted with ether. The ether extract is washed successively with dilute hydrochloric acid, water, dilute sodium bicarbonate solution, water and dried over magnesium sulfate. The organic solvent is removed by vacuum distillation and the residue recrystallized from methanol to yield 19-nor-3a,5ot-cycloandrostane-6/3,17/5- diol 6,17-diacetate (III').

Following the procedure of Preparation 19 but substituting for acetic anhydride another anhydride, such as propionic, butyric, valeric, hexanoic, trimethylacetic, isobutyric, isovaleric, cyclohexanecarboxylic, p-hexylpropionic, benzoic, phenylacetic, acrylic, crotonic, undecylenic, propiolic, cinnamic, maleic, citraconic, etc., yields, respectively, the corresponding l9-nor-3ot,5a-cycloandrostane-6B,17fl-diol 6,17diacy1ate (III').

If desired, the diacylation can be conducted for about six hours at reflux and with additional procedures such as chromatography or fractional crystallization.

M PREPARATION 20 Following the procedure of Preparation 19, but substituting 3a,5a-cycloandrostane-6[3,17,8-diol (III') (obtained in Preparation 12) as starting material, yields 3a,5a-cycloandrostane-6fl,l7B-diol 6,17-diacetate (111').

Following the procedure of Preparation 20 but substituting for acetic anhydride another anhydride such as isobutyric, trimethylpropionic, phenylvaleric, cinnamic, citraconic, etc., yields, respectively, the corresponding 3a,5a-cycloandrostane-6fi,17,8-diol 6,17diacylate (III').

PREPARATION 21 19-n0r-3a,5a-cycl0andr0stane-6,1 7-di0ne (IV) A solution of 0.1 g. of 6p-hydroxy-l9-nor-3a,5 x-cycloandrostan-l7-one (III) (obtained in Preparation 9) in 25 ml. of acetone is cooled in an ice bath and 1 ml. of Jones reagent (8 N chromium trioxide in concentrated sulfuric acid diluted with water, prepared as in J. Org. Chem. 21, 1547) added. After about 10 minutes, the excess oxidant is destroyed by the addition of 1 ml. of isopropyl alcohol. Water is added and the acetone evaporated under a stream of nitrogen. The precipitated product is collected on a filter, washed with water and dried to yield 19-nor- 3a,5a-cycloandrostane-6,17-dione (IV).

PREPARATION 22 3 11,5 a-cycl0andr0stane-6J 7-d1'0ne (IV) Following the procedure of Preparation 21 but substituting 6fl-hydroxy-3a,5a-cycloandrostan-l7-one (III) (obtained in Preparation 10) as starting material, yields 3a,5a-cycloandrostane-6,17-dione (IV).

PREPARATION 23 17,8-hydroxy-19-n0r-3a,5a-cycloandrostan-6-one (l V) A solution of 0.1 g. of 19-nor-3a,5a-cycloandrostane- 613,17fi-di01 (III') (obtained in Preparation 11) in 10 ml. of ethyl acetate is shaken for about 72 hours with 1 g. of manganese dioxide, prepared in accordance with the procedure described in J. Chem. Soc. 1104 (1951). After the shaking period, the mixture is filtered, the filter cake washed with three 1 ml. portions of ethyl acetate, the filtrate and additional ethyl acetate washings combined, and the solvent removed under vacuum. The crystalline residue obtained is dissolved in methylene chloride and chromatographed over a column of Florisil to give 17,8- hYdI'OXY-I.9-IlOr-30L,50t-CyClOaIldIOSIaH-6-Ol'l6 (IV).

PREPARATION 24 17fl-hydr0xy-3a,5u-cycl0andr0stan-6-0ne (IV) Following the procedure of Preparation 23 but substituting 3a,5a-cycloandrostane-6fl,l7 3-diol (III') (obtained in Preparation 12) as starting material, yields 17/3-hydroxy-3a,5a-cycloandrostan-6-one (IV).

PREPARATION 25 1 7,8-hydroxy-1 7u-meth yZ-I 9-n0r-3 41,5 a-cycI0- androstan-tS-one (IV) A solution of 0.1 g. of Not-methyl-19-nor-3a,5a-cycloandrostane6fl,l7B-diol (III') (obtained in Preparation 13) in 25 ml. of acetone is cooled in an ice bath and 1 ml. of Jones reagent added. After about 10 minutes the excess oxidant is destroyed by the addition of 1 ml. of isopropyl alcohol. Water is added and the acetone evaporated under a stream of nitrogen. The precipitated product is collected on a filter, washed with water and dried to yield 17fl-hydroxy-17a-methyl-19-nor-3u,5e-cycloandrostan-G-one (IV).

Following the procedure of Preparation 25 but substituting other corresponding 17a-alkyl compounds (III') as starting materials, such as 15 (1 17u-ethyl-10-nor-3 a,5a-cycloandrostane-6p,175-

diol (III'), (2) 17a-butyl-19-nor-3a,5a-cycloandrostane-6(3,17,6-

diol (HI'), (3) 17a-undecyl-19-nor-3a,5a-cyc1oandrostane-6B,17B-

diol (III), etc.,

yields, respectively,

(1 17p-hydroxy-17a-ethyl-19-nor-3a,5a-cycloandrostan-6-one (IV),

(2) 17,8-hydroxy-l7a-butyl-l9-nor-3a,5a-cycloandrostan-6-one (1V),

(3) 17fi-hydroxy-17u-undecyl-19-nor-3u,5a-cycloandrostan-6-one (IV), etc.

PREPARATION 26 1 7 3-hydroxy-1 7 a-methyl-fluj a-cycloandrstan-6-0ne (IV) Following the procedure of Preparation 25 but substituting 17OL-II16Ihyl 3a,5a cycloandrostane-Gfl,17/3-dio1 (III) (obtained in Preparation 14) as starting material, yields 17B-hydroxy 17oz methyl-3a,5a-cycloandrostan- 6-one (IV).

Following the procedure of Preparation 26 but substituting other corresponding 17a-alky1 compounds (III) as starting materials, such as 1) 17a-propyl-3a,5a-cycloandrostane-6 3,17,8-diol (2) 17a-pentyl-3u,5oc-cycloandrostane-6fi,17fl-diol (3) 17a-dodecyl-3a,5a-cycloandrostane-6B,17B-diol (III), etc.,

yields, respectively,

(1 17B-hydr0xy-17a-propyl-3a,5a-cycloandrostan- 6-one (IV),

(2) 17;3-hydroxy-17a-pentyl-3a,5a-cycloandrostan- 6-one (IV),

(3) 17p-hydroxy-17a-dodecyl-3a,5u-cycloandrostan- 6-0ne (IV), etc.

PREPARATION 27 1 7,8-hydroxy-1 7a-erhynyl-19-nor-3a,5a-cycloand rostan-o-one (IV) A solution of 0.1 g. of 17u-ethynyl-19-nor-3aim-cycloandrostan-6/3,17,6-diol (III') (obtained in Preparation 15) in 15 ml. of acetone is cooled in an ice bath and 1 ml. of Jones reagent added. After about minutes the excess oxidant is destroyed by the addition of 1 ml. of isopropyl alcohol. Water is added and the acetone evaporated under a stream of nitrogen. The precipitated product is collected on a filter, washed with water and dried to yield 17 8- hydroxy 17a ethynyl 19 nor-3 a,5a-cycloandrostan-6- one (IV).

Following the procedure of Preparation 27 but substituting other corresponding 17a-alkynyl compounds (III) as starting materials, such as yields, respectively,

(1) 17,6-hydroxy-17a(1-propyny1-19-nor-3a,5a-

cycloandrostan-G-one (IV),

(2) 17,8-hydroxy-17 OL( 1-butynyl)- l9-nor-3 04,5 a-cycloandrostan-6-one (IV),

(3) 17 ,B-hydroxy-17 a-trifluoromethylethynyl-19-nor- 3u,5u-cycloandrostan-6-one (IV), etc.

16 PREPARATION 2s 1 7,8-hydroxy-1 7oz-ethynyl-3 01,5 a-cycloandrostan- 6-one (IV) Following the procedure of Preparation 27 but substituting 17a-ethynyl 30:,50c cycloandrostane-6fl,17B-diol (III) (obtained in Preparation 16) as starting material yields 176 hydroxy 17oz ethynyl-3a,5a-cycloandrostan- 6-one (IV).

Following the procedure of Preparation 28 but substituting other corresponding 17a-alkynyl compounds (III') as starting materials, such as (1) 17a( l-butynyl)-3a,5 zx-cycloandrostane- 6B,17;3-diol (III),

(2) l7a-trifluoromethylethynyl-3flu-cycloandrostane-6/3,17fl-diol (III'),

(3 17a-chloroethynyl-3a,5a-cycloandrostane- 65,17B-dio1 (III'), etc.,

yields, respectively,

(1) 17fi-hydroxy- 17a 1-butynyl)-3a,5u-cycloandrostane-6-one (IV),

(2) 17B-hydroxy-17ot-trifluoromethylethynyl-304,5-

cycloandrostan-6-one (IV),

(3 17,8-hydroxy- 17 a-chloroethynyl-3 a,5 a-cycloandrostan-6-one (IV), etc.

PREPARATION 29 A solution of 0.1 g. of 17a-vinyl-19-nor-3a,5a-cycloandrostan-6B,17;8-diol (III) (obtained in Preparation 17; in 25 ml. of acetone is cooled in an ice bath and 1 ml. of Jones reagent added. After about 10 minutes the excess oxident is destroyed by the addition of 1 ml. of isopropyl alcohol. Water is added and the acetone evaporated under a stream of nitrogen. The precipitated product is collected on a filter, washed with water and dried to yield 17 8-hydl'OXy-170t-VII1Y1-19-I1OY-3 04,5 a-cycl0androstan6-one (IV) Following the procedure of Preparation 29 but substituting other corresponding l7a-alkenyl compounds III) as starting materials, such as (2) 1704(4-(16C611Yl) 19-nor-3 a,5a-cycloandrostan- 65,17fi-diol (III),

(3 17a-trifluoromethylvinyl-19-nor-3 0:,5ot-CYC1O- androstane-6fi,17B-diol (111), etc.,

yields, respectively,

(1) 17,B-hydroxy-17a( 3-octenyl)-l9-nor-3a,5acycloandrostan-G-one (IV),

(2) 17 fl-hydroxy- 1 7 on 4-decenyl 19-I1013a,5 a-cycloandrostan-6-0ne (IV),

(3) 17li-hydroxy-trifiuoromethylvinyl-19-nor-3a,5a-

cycloandrostan-6-one (IV), etc.

PREPARATION 3 0 I 7fi-hyd'r0vcy-1 7 ot-vinyl-3 oc,5 a-cycloandrostan- 6-0ne (IV) Following the procedure of Preparation 29' but substituting 17m-vinyl 3a,5o cycloandrostan- 6,8,17,5 diol (III') (obtained in Preparation 18) as starting material, yields 17,8-hydroxy-17rx-vinyl-3a,5u-cycloandrostan-6-one (IV).

Following the procedure of Preparation 30 but substituting other corresponding 17a-alkenyl compounds (III') as starting materials, such as (1) 17 0c l-propenyl -3 04,5oc-CYCIO2111dI'OStfiI16- 65,17,8-diol (III (2) 17 a-trifluoromethylvinyl-3 a,5a-cycloandrostane- 66,17,8-diol (III'), etc.,

yields, respectively,

1 7 (1) 17B-hydroxy-17a(1-propenyl)-3a,5a-cycloandrostan-6-one (IV), (2) 17B-hydroxy-17a-trifluoromethylvinyl-3add-cycloandrostan-6-one (IV), etc.

PREPARATION 31 1 7,8-hydroxy-19-n0r-3oc,5a-cycl0androstan-6-0ne 1 7-acetate (IV) A solution of 0.2 g. of 19-nor-3a,5a-cycloandrostane- 6;8,17;3-dio1 6,17-diacetate (I II) (obtained in Preparation 19) in 10 ml. of acetone is cooled to about 10 C. and 2 ml. of Jones reagent added with swirling. The mixture is kept for about 16 hours at about C., then poured into iced water and the resulting suspension filtered. The solid material on the filter is washed with water, dried and crystallized from methanol to give 17,8-hydroxy-19-nor- 3a,Su-cyclQandrOstan-G-one 17-aoetate (IV).

Following the procedure of Preparation 31 but substituting other 19-nor-3a,5u-cycloandrostane-6,3,175-diol 6,17-diacylates (111), such as the corresponding 6,17-dipropionate; 6-butyrate, 17-isovalerate; 6,17-dibenzoate; o-p-hexylpropionate, l7-cinnamate; 6,17-diundecylenate; 6-propiolate, 17-acetate; 16,17-dicrotonate, etc., yields the corresponding 19-nor-3a,5a cycloandrostan-17/3-ol-6-one 17-acylate (IV).

PREPARATION 32 1 7 ,8-hydr0xy-3 a,5 ot-cycloandrostan-6-one 1 7 -acetate (IV) Following the procedure of Preparation 31 but substituting 3a,5a-cycloandrostane-6,B,17fi-diol 6,17-diacetate (III') (obtained in Preparation 20) as starting material, yields 17p-hydroxy-3u,5a-cycloandrostan-6-one 17-acetate (IV).

Following the procedure of Preparation 32 but substituting other 3a,5a-cycloandrostane-6fi,17fl-diol 6,17-diacylates (111) such as the corresponding 6,17-dibutyrate; 6-valerate, 17-hexanoate; 6,17-diphenylacetate; 6-acrylate, 17-maleate; 6,17-dicitraconate; G-cinnamate, 17-propionate; 16,17-didecylenate, etc., yields the corresponding 17fi-hydroxy-3a,5a-cycloandrostan-6-one 17-acylate (IV).

PREPARATION 33 1 7p hydroxy-19-n0r-3a,5a-cycl0andr0otan-6-one 17-acetare (IV) A solution of 0.7 g. of 17/3-hydroxy-l9-nor-3a,5a-cycloandrostan-G-one (IV) (obtained as in Preparation 12) in 1.4 ml. of pyridine and 0.7 ml. of acetic anhydride is kept at room temperature for about 16 hours. Water is slowly added to the reaction mixture and the product extracted with methylene chloride, washed with aqueous sodium chloride solution until nearly neutral, dried and the solvent removed. The residue is chromatographed through a column of Florisil to give 17fi-hydroxy-19-nor-3a,5a-cycloandrostan-6-one l7-acetate (IV).

Similarly, by reacting 17fl-hydroxy-19-nor-3mafia-cycloandrostan-6-one (IV) with the appropriate hydrocarbon carboxylic acid anhydride, for example, at temperatures between about 30 and 150 C. using the above procedure there are produced other l7-acylates thereof such as 17- propionate, 17-butyrate, 17-valerate, 17-hexanoate, 17-trimethylacetate, 17-isobutyrate, 17-isovalerate, l7-cyclohexanecarboxylate, l7-cyclopentylpropionate, 17-phenylpropionate, 17-p-hexyloxypropionate, 17-benzoate, 17-hemisuccinate, 17-phenylacetate, 17-acrylate, 17-crotonate, 17- undecylenate, 17-propiolate, 17-cinnamate, 17-maleate and 17-citraconate.

PREPARATION 34 17,8-hydr0xy-3a,5a-cycl0androstan-6-0ne 17-acetate (IV) Following the procedure of Preparation 33 but substituting 17fl-hydroxy-3a,5a-cycloandrostan-6-one (IV) (obtained as in Praparation 14) as starting material, yields 175-hydroxy-3a,5a-cycloandrostan-6-one 17-acetate (IV). Following the procedures of Preparation 34 and the paragraph immediately preceding it, yields other 17-acylates of 17fi-hydroxy-3a,5ot-cycloandrostan-6-one (IV), e.g., its 17-butyrate, 17-isovalerate, 17-phenylacetate, 17- propiolate, etc.

PREPARATION 35 mg. of 19-nor-3a,5ot-cycloandrostan-17,9-ol-6-one l7-acetate (IV) (obtained in Preparation 33) is dissolved in 4 ml. of 5% potassium hydroxide in methanol, followed by the addition of 4 drops of water. After standing for about 16 hours at room temperature, the solution is warmed on a steam bath and diluted to incipient crystallization by the dropwise addition of water. Recrystallization of this material from alcohol and water gives pure 17fl-hydroxy-19-nor-3a,5 a-cycloandrostan-6-one (IV).

Following the procedure of Preparation 35 but sustituting other 17-acylates of Uri-hydroxy-19-n0r-3a,5a-cycloandrostan-6-one (IV) as starting materials, e.g., those recited in the paragraph immediately preceding Preparation 34, also yields l7t3-hydroxy-l9-nor-3a,5a-cycloandrostan-6-one (IV).

PREPARATION 36 Following the procedure of Preparation 35 but substituting 17,B-hydroxy-311,5a-cycloandrostan-6-one 17-acetate (obtained in Preparation 34) as starting material, yields 17,6-hydroxy-3u,5a-cycloandrostan-6-one (IV).

Following the procedure of Preparation 36 but substituting other l7-acylates of 17fi-hYdIOXy-3uSu-CYCIOaIIdI'O- stan-6-one (IV) as starting material, e.g. those recited in the paragraph immediately preceding Preparation 34, also yields 17B-hydroxy-3a,5ot-cycloandrostan-6-one (IV).

PREPARATION 37 1 7p hydroxy-1 7a-methyl-19-nor-3a,5acycl0andr0stan-6- one 17-acetate (IV) A solution of 0.7 g. of 17,8-hydroxy-17a-methyl-19-nor- 3a,5,a-cycloandrostan-17a-methyl-6-one (IV) (obtained as in Preparation 25) in 1.4 m. of pyridine and 0.7 ml. of acetic anhydride is heated at about 80 C. for about 16 hours. Water is slowly added to the reaction mixture and the product extracted with methylene chloride, washed with aqueous sodium chloride until nearly neutral, dried and the solvent removed. The oily residue is chromatographed through a column of Florisil giving flit-hydroxy- 1711 methyl-19-nor-3a,5a-cycloandrostan-6-one 17-acetate (IV).

Similarly, by reacting 17/3-hydroxy-l7a-methyl-19-nor- 3at,5a-cycloandrostan-6-one (IV) with the appropriate hydrocarbon carboxylic acid anhydride, for example, at temperatures between about 60 and C. using the above procedure there are produced other 17-acylates thereof such as l7-propionate, 17-butyrate, 17-valerate, 17- hexanoate, 17-trimethylacetate, 17-isobutyrate, 17-isovalerate, 17-cyclohexanecarboxylate, 17-cyclopentylpropionate, 17-phenylpropionate, 17-p-hexyloxy-B propionate, 17-benzoate, l7-phenylacetate, 17-acrylate, 17-crotonate, 17-undecylenate, 17-propiolate, and 17-cinnamate.

Following the procedures of the immediately preceding paragraph and of Preparation 37 but substituting other coresponding 17-alkyl starting compounds (IV) and other acid anhydrides of hydrocarbon carboxylic acids, such as (1) hydroxy 17a-dodecyl-19-nor-3a,5ot-cyc1oandrostan-6-one (IV) and propionic anhydride,

(2) 17fi-hydroxy-17ot-pentyl-19-n0r-3a,5ot-cycloandrostan- 6-one (IV) and benzoic anhydride,

(3) 17,6 hydroxy-17a-ethyl-19-nor-3u,5a-cycloandrostan- 6-one (IV) and cyclopentylpropionic anhydride, etc.,

yields respectively,

(1 17,6 hydroxy 17rx-dodecyl-l9-nor-3a,5a-cycloandrostan-6-one 17-propionate (IV),

(2) 17fi-hydroxy-17a-pentyl-19-nor-3u,5a-cycloandrostan-' PREPARATION 38 3a,5a-cycl0androstane-17a-mezhyl-l7 8-ol-6-one 1 7-acetate Following the procedure of Preparation 37 but substituting 17B hydroxy 17a-methyl-3a,5a-cycloandrostan-6- one (IV) (obtained in Preparation 16) as starting material, yields 1713 hydroxy 17a-methy1-3a,5a-cycloandrostan-6one 17-acetate (IV).

Following the procedures of Preparation 38 and the two paragraphs immediately preceding it, yields other 176- hydroxy-17a-alkyl-3u,5u-cycloandrostan 6 one 17-acylates (IV), e.g., 17 3-hydroxy-butyl-3aim-cycloandrostan- 6-one l7-hexanoate (IV), 17B-hydroxy-17a-heptyl-3a,5acycloandrostan 6-one 17-phenylbutyrate (:IV), 17fl-hydroxy-17a-decy1-3a,5 a.-cycloandrostan-6-one 17-dodecanoate (IV), etc.

PREPARATION 39 1 7,8-hydroxy-1 7a-ethynyl-19-n0r-3a,5a-cycl0andr0stan 6-0ne-17-acetate (IV) A solution of 0.7 g. of 17,8-hydroxy-17a-ethynyl-l9 nor- 3a,5a-cycloandrostan-6-one ('IV) (obtained as in Preparation 17) in 1.4 ml. of pyridine and 0.7 m. of acetic anhydride is heated at about 60 C. for about 16 hours. Water is slowly added to the reaction mixture and the product extracted with methylene chloride, washed with aqueous sodium chloride until nearly neutral, dried and the solvent removed. The oily residue is chromatographed through a column of Florisil to give 17fl-hydroxy-17a-ethynyl-l9 nor-3a,5a.-cycloandrostan-6-one 17-acetate (IV).

Similarly, by reacting 17fi-hydroxy-17a-ethynyl-19-nor- 3a,5a-cycloandrostan-6-one (IV) with the appropriate hydrocarbon carboxylic acid anhydride, for example, at temperatures between about 30 and 150 C. using the above procedure there are produced other 17-acylates thereof such as 17-propionate, 17-butyrate, 17-valerate, l7- hexanoate, 17-trimethylacetate, 17-isobutyrate, l7-isovalerate, 17 cyclohexanecarboxylate, 17 cyclopentylpropionatc, 17-phenylpropionate, 17-p-hexyloxypropionate, 17-benzoate, 17-phenylacetate, 17-acrylate, l7-crotonate, 17-undecylenate, 17-propiolate, 17-cinnamate, 17- maleate and 17-citracon'ate.

Following the procedures of the immediately preceding paragraph and of Preparation 39 but substituting other corresponding 17a-alkynyl starting compounds 1V) and other acid anhydrides of hydrocarbon carboxylic acids, such as 1 17fl-hydroxy-17a(2-butynyl) -19-nor-3 :,5oc-CYC10- androstran-G-one (IV) and isovaleric anhydride,

(2) 17fi-hydroxy-17u-chloroethynyl-19-nor-3 a,5a-cycloandrostan-6-one (IV) and hexyloxypropionic anhydride,

(3) 17fl-hydroxy-17a-trifluoromethylethynyl-19-nor- 3a,5a-cycloandrostan-6-one (IV) and acrylic anhydride, etc.,

yields, respectively,

( 1 17fl-hydroxy-17u(2-butynyl)-19-nor-3a,5a-cycloandrostan-6-one 17-isovalerate (IV),

(2) 17/8-hydroxy-17wchloroethynyl-19-nor-3aim-cycloandrostan-6-oue 17-hexyloxypropionate (IV), (3) 17,8-hydroxy-17a-trifiuoromethylethynyl-19-nor- 3a,5a-cycloandrostan-6-one 17-acrylate (IV), etc.

PREPARATION 40 17,8-hydr0xy-1 7 a-alkynyl-3a,5 tat-cycloandrostan- 6-one 1 7-acetate (IV) Following the procedure of Preparation 39 but substituting 17fi-hydroxy-17a-ethynyl-3aim-cycloandrostan- 6-one (IV) (obtained in Preparation 28) as starting material, yields 17fl-hydroxy-17u-ethynyl-3a,5a-cycloandrostan-6-one 17-acetate (IV).

Following the procedures of Preparation 40 and the two paragraphs immediately preceding it, yields other 17(3- hydroxy-17a-alkynyl-3a,5a-cycloandrostan-6-one 17-acylates (*IV), e.g., 17 3 hydroxy-17a.(2-propynyl)-3a,5a-cycloandrostan 6 one 17-propionate, 17 3-hydroxy-l7ubromoethynyl 3u,5 x cycloandrostan-6-one 17-phenylacct-ate, 17,8 hydroxy-l7a-trifluoromethylethynyl-304,50;- cycloandrostan-G-one 17-benzoate (IV), etc.

PREPARATION 41 1 7,8-hydr0xy-1 7a-vinyl-19-n0r-3aim-cycloandrostan- 6-0ne 17-acetate (IV) To a solution 0.1 g. of 17/8-hydroxy-l7a-vinyl-19 nor- 3a,5a-cycloandrostan-6-one (IV) (obtained in Preparation 19) in 5 m. of methylene chloride and 0.1 ml. of pyridine, 0.1 g. of acetyl chloride is added. After standing for about 1.25 hours at room temperature, the solution is Washed successively with water, dilute acid, dilute base, water, dried over magnesium sulfate and the solvent removed. The residue is chromatographed over a column of Florisil and crystallized from acetone-Skellysolve B to give 17 3-hydroxy-17a-vinyl-19-nor-3a,5a-cycloandrostan- 6-one 17-acetate (IV).

Following the procedure of Preparation 41 but substituting other 17a-alkenyl compounds (IV) as starting materials and other appropriate halides or anhydrides of hydrocarbon carboxylic acids, such as 1 17fi-hydroxy-17u.(2-butenyl) -19-nor-3 a,5a-cycloandrostan-G-one (IV) and valeryl chloride,

(2) 17;8-hydroxy-17a(l-propenyl)-19-nor-3a,5a-cycloandrostan-6-one (IV) and hexanoic anhydride, (3) 17fl-hydroxy-17a-trifluoromethylvinyl-l9-nor-3u,5acycloandrostan-G-one IV) and isobutyryl chloride,

etc.,

yields, respectively,

( 1 17l3-hydroxy-17a.( Z-bllteIlYD-19-I10f-3a,5oc-CYC10- androstan-6-one 17-valerate (IV),

(2) 17B-hydroxy-17u( 1-propenyl) -19-110I-30t,5a-CYC10- androstan-6-one 17-hexanoate (IV),

(3 17fl-hydroxyl7a-trifluoromethylvinyl- 19-110r-3oc,5ot-

cycloandrostan-6-one 17-isobutyrate (IV), etc.

PREPARATION 42 17fl-hydroxy-I 7 ot-vinyl-j 04,5 (it-cycloandrostan- 6-0ne 1 7-acetate (IV) PREPARATION 43 7-methylene-1 9-nor-3 (1,5 a-cycl0andr0stane-6J 7 dione (V) A mixture of 0.4 g. of 19-nor-3a,5a-cycloandrostane- 6,17-dione (IV) (obtained in Preparation 21), 0.2 g. of dimethylammonium chloride, 0.8 g. of paraformaldehyde and 70 ml. of dioxane is stirred with heating at reflux temperature for about 4 hours and poured into about 700 ml. of water. The resulting precipitate is collected, dissolved in methylene chloride and the solution washed first with dilute aqueous hydrochloric acid and then Water.

Evaporation of the methylene chloride and crystallization of the residue from diisopropyl ether gives the product, 7 methylene 19-nor-3a,5o-cycloandrostane-6,l7-dione (V).

PREPARATION 44 7-methylene-3a,5a-cycl0andr0stan'e-6J7-dione (V) Following the procedure of Preparation 43 but substituting 3a,5a-cyc1oandrostane-6,17-dione (IV) (obtained in Preparation 22) as starting material, yields 7-methylene- 301,5 a-cycloandrostane-6, 17-dione (V).

PREPARATION 45 Following the procedure of Preparation 43 but substituting 17,8 hydroXy-19-nor-3a,5u-cycloandrostan-6-one 17-acetate (IV) (obtained in Preparation 33) as starting material, yields 17fi-hydroxy 7 methylene-19-nor-3a,5etcycloandrostan-6-one 17-acetate (V).

Similarly, substituting other 17-acylates of 17,8-hydroxy- 19-nor-3a,5a-cycloandrostan-6-one (IV), such as the 17- propionate, 17-trimethylacetate, 17-isovalerate, 17-phenylacetate, 17-crotonate, 17-benzoate, 17-hemisuccinate, etc., for the 17-acetate employed as starting material in the preceding paragraph, yields the corresponding 17/i-hydroxy-7-methylene-19-nor-3 D,50t-CYC1021HdIOSlI3I1-6-Ol16 17- acylate (V).

PREPARATION 46 17,6-hya'r0xy 7 methylene-3a,5u-cycl0andr0stan-6-0ne 17-acetate (V) Following the procedure of Preparation 43 but substituting 17fl-hydroxy-3a,5a-cycloandrostan-6-one 17-acetate (IV) (obtained in Preparation 34) as starting material, yields 17!? hydroXy-7-methylene-3 a,5a-cycloandrostan-6-one 17-acetate (V).

Substituting other 17 acylates of 17,8-hydroxy3a,5ucycloandrostan-o-one (IV), such as the 17-butyrate, 17- valerate, 17-propiolate, etc., for the 17-acetate employed as starting material in the preceding paragraph, yields the corresponding 17;; hydroxy 7 methylene-3 mafia-cycloandrostan-6-one 17-acylate (V).

PREPARATION 47 17,8-hydrxy 7 methylene-19-n0r-3uJa-cyclaandrostan- 6-0ne (V) Following the procedure of Preparation 43 but substituting 17 8 hydroxy-19-nor3a,5a-cycloandrostan-6-one (IV) (obtained in Preparation 35) as starting material, yields 17;? hydroxy 7 methylene 19 nor-3a,5a-cycloandrostan-6-one (V).

PREPARATION 48 J 7 ,B-hydroxy-7-methylene-3 (1,5 ot-cycloandrostan-fi-one (V) Following the procedure of Preparation 43 but substituting 175 hydroXy-3u,5ot-cycloandrostan-6-one (IV) (obtained in Preparation 36) as starting material, yields 17,8 hydroxy 7 methylene 3a,5a cycloandrostan-6- one (V).

PREPARATION 49 17,8-hydroxy 17 O6 methyl 7 methylene-19-n0r-3u,5acycl0andr0stan-6-0ne (V) Following the procedure of Preparation 43 but substituting 17,8-hydroxy 17oz methyl-19-nor-3a,5u-cyc1oandrostan-6-one (IV) (obtained in Preparation as starting material, yields 17fi-hydroxy-17a-n1ethy1-7-methylene-19-nor-3 oc,5 a-cycloandrostan-6-one (V).

Following the procedure of Preparation 49 but substituting other corresponding 17a-a1kyl compounds (IV) as starting materials, such as 22 (1) 17,8-hydroxy-17a-ethyl-19-nor-3ot,5rx-cycloandrostan-6-one (IV) (2) 17B-hydr0xy-17a-undecyl-l9-nor-3a,5a-cycloandrostan-6-one (IV), etc.,

yields, respectively,

(1) 17,8-hydroxy-17a-ethy1-7-metl1ylene-19-nor-3 11,51

cycloandrostan-6-one (V) (2 17/3-hydroxy-17u-undecyl-7-methylene-19-nor- 3 a,Sa-cycloandrostan-17a-undecyl-6-one (IV), etc.

PREPARATION 50 17,6 hydroxy-l 7a-methyl-7-methylene-3a,5a-cycl0andro- Stan-1 7 a-methyl-6-0ne (V) Following the procedure of Preparation 43 but substituting hydroxy-17a-methyl-3a,5a-cycloandrostan- 6-one (IV) (obtained in Preparation 16) as starting material, yields 17,8-hydroxy-17a-methyl-7-methylene-3a,5acycloandrostan-G-one (V).

Following the procedure of Preparation 50 but substituting other corresponding 17a-alky1 compounds (IV) as starting materials, such as 1) 17 ,B-hydroxy- 17 ot-isopropyl-3a,5 tx-cycloandrostan- 6-one (IV),

(2) 17 5-hydroxy- 17 u-dodecyl-3 0:,5 a-cycloandrostan- 6-one (IV), etc.,

yields, respectively,

( 1) 17fl-hydroxy- 17u-isopropylJ-methylene-301,50:-

cycloandrostan-6-one (V),

(2) 17fi-hydroxy-17a-dodecyl-7-Inethylene-3a,5a-

cycloandrostan-6-one (V), etc.

PREPARATION 51 17,8 hydroxy 17a methyl-7-methylene-I9-nor-3og5occycl0andr0stan-6-0ne 17-acetate (V) 1) 17,6-hydroxy-17a-hexyl-19 nor-3 a,5a-CyC10al1dI'O- stan-6-one 17-valerate (IV),

(2) 17fi-hydroxy-17ot-decyl-19-nor-3a,5a-cycloandro stan-6-one 17-benzoate (IV),

(3) 17 B-hydroXy-17 wethyl-19-nor-3 a,5a-CyClOaI1drO- stan-6-one 17-cyclopentylpropionate (IV), etc.,

yields, respectively,

( 1 17 B-hydroxy17u-hexyl-7-methy1ene-19-nor-3 04,50:-

cycloandrostan-6-one 17-valerate (V),

(2) 17fi-hydroxy-17a-decyl-7-methylene-19-nor- 3a,5ot-cycloandrostan-6-one 17-benzoate (V),

( 3 17fl-hydroxy-17a-ethyl-7-methylene-19-nor- 3a,5ot-cycloandrostan-6-one 17-cyclopentylpropionate (V).

PREPARATION 52 17,8 hydroxy-I 7a-methyl-7-methylene-3a,5a-cycl0androstan-d-one 17-acetate (V) Following the procedure of Preparation 43 but substituting 17,8 hydroxy-17a-methyl-3a,5 x-cycloandrostan- 1 17 ,8-hydroxy-17 a-isobu-tyl-3a,Sat-cycloandrostan- 6-one 17-benzoate (IV),

(2) 17fi-hydroxy-17a-octyl-3a,5a-cycloandrostan- 6-one 17-isovalerate (IV),

(3) 17fi-hydroxy-17a-dodecyl-3Jot-cycloandrostan- 6-one 17-cyclopentylpropionate (IV), etc.,

yields, respectively,

( 1 17/3-hydroXy-17a-isobutyl-7-methylene-3a,5a-

cycloandrostan-6-one 17-benz0ate (V),

(2) 17fl-hydroxy-17a-octyl-7-methylene-3u,5acycloandrostan--one 17-isovalerate (V),

(3) 17B-hydroxy- 17 a-dodecyl-7 -methylene-3 ,5 a-cycloandrostan-6-one 17-cyclopentylpropionate (V), etc.

PREPARATION 53 1 7fl-hydr0xy-1 7 u-ethynyl-7 -methy lene-l 9-n0r-3 01,5 acycloandrostan-6-0ne (V) Following the procedure of Preparation 43 but substituting 17,8-hydroxy 17oz ethynyl 19 nor-3a,5a-cycloandrostan-6-one (IV) (obtained in Preparation 17) as starting material, yields 17fi-hydroxy 17a ethynyl-7- methylene-19-nor-3a,iwcycloandrostan-6-one (V).

Following the procedure of Preparation 53 but substituting other corresponding 17oz alkynyl compounds (IV) as starting materials, such as (1) 17/3-hydroxy-17a(1-butynyl)-19-n0r-3u,5a-

cycloandrostan-6-one (IV),

(2) 17,8-hydroxy-17a-trifluoromethylethynyl-19-nor 3a,5a-cycloandrostan-6-one (IV), etc.,

yields, respectively,

(1) 17fi-hydroXy-17u( l-butynyl)-7-methylene-l9-nor- 3 04,5 a-cycloandrostan-6-one (V),

(2) 17 ,B-hydroxyl7wtrifluoromethylethynyl-7-methylene-19-nor-3a,5 a-cycloandrostan-6-one (V), etc.

PREPARATION 54 1 7fl-hydroxy-1 7 a-ethynyl-7 -methylen -3 0:,5 occycloandrostan-6-one (V) Following the procedure of Preparation 43 but substituting 17B hydroxy-17a-ethynyl 304,511 cycloandrostan-6-on'e (IV) (obtained in Preparation 18) as starting material, yields 17B-hydroxy 17oz ethynyl 7 methylcue-3u,5a-cyc1oandrostan-6-one (V).

Following the procedure of Preparation 54 but substituting other corresponding 17a alkynyl compounds (IV) as starting materials, such as 1 17B-hydroxy-17a(1-propyny1)-3 06,50L-CYC- androstan-6-one (IV),

(2) 17,8-hydroxy-17a-chloroethynyl-3 06,50t-CYC10- androstan-6-one (IV), etc.,

yields, respectively,

(1 17fl-hydroxy-17a( l-propynyl)-7-methylene-3a,5a-

cycloandr0stan-6-one (V),

( 2) 17p-hydroxy-17a-chloroethynyl-7-methylene- 304,5a-cycloandrostan-6-one (V), etc.

24 PREPARATION 55 1 7B-hydr0xy-1 7a-ethynyl-7-methylene-1 9-n0r-3 04,50:- cycl0andr0stan-6-0ne 1 7-acetate (V) Following the procedure of Preparation 43 but substituting 17B-hydroxy 17cc ethynyl-19-nor-3a,5o-cycloandrostan-6-one 17-acetate (IV) (obtained in Preparation 39) as starting material, yields 17fl-hydroxy-17ot-ethynyl- 7 methylene-19-nor 30:,504 cycloandrostan-6-one 17- acetate (V).

Substituting other l7-acylates of 17,8 hydroxy-17aethynyl 19 nor 30,5oc cycloandrostan 6 one (IV), such as the 17-propi0nate, l7 undecanoate, 17-phenylacetate, 17 hexanoate, 17 phenyloctanoate, etc., for the 17-acetate compound employed as starting material in the preceding paragraph, yields the corresponding 17,8-hydroxy 17a ethynyl 7 methylene-19-nor-3a,5 x-cyclo androstan-G-one l7-acylate (V).

Following the procedure of Preparation 55 but substituting other corresponding Not-alkynyl 17-acylate compounds (IV) as starting materials, such as 1 17fi-hydr0Xy-1.7a( l-propynyl) l9-11OI-3oc,5oL-Cycloandrostan-6-one 17-acetate (IV),

(2 17fl-hydr0xy-17a-trifiuoromethylethynyl-19-nor- 3a,5a-cycloandrostan 6-one 17-propionate (IV), etc.,

yields, respectively,

( 1 17/3-hydroxy-17u( l-propynyl)-7-methylene-19-nor- 3a,5a-cycloandrostan-6-one 17-acetate (V),

(2) 17,8-hydroxy-17wtrifluoromethylethynyl-7-methylene-19-nor-3a,5a-cycloandrostan-l7a-trifluoromethy1ethynyl-6-one l7-propionate (V), etc.

PREPARATION 5 6 1 7 fl-hydroxy-I 7u-ethynyl-7-m ethylene-311,50- icycl0andr0stan-6-0ne 1 7-acetate V) Following the procedure of Preparation 43 but substituting 17,8 hydroxy 17a ethynyl 300,504 cycloandrostan-6-one 17-acetate (IV) (obtained in Preparation 40) as starting material, yields 17B-hydroxy-17a-ethynyl- 7-methylene-3a,5a-cycloandrostan-6-one 17-acetate (V).

Substituting other 17-acylates of 17,8 hydroxy-l7uethynyl 30,5oz cycloandrostan-6-one (IV), such as the 17-butyrate, 17-octanoate, 17-phenylacetate, l7-valerate, etc. for the 17-acetate employed as starting material in the preceding paragraph, yields the corresponding 17B- hydroxy a ethynyl 7 methylene 30,5oc cycloandrostan-6-one 17-acylate (V).

Following the procedure of the immediately preceding paragraph and of Preparation 56 but substituting other representative corresponding 17a alkynyl 17 acylates (IV), such 1 17,6-hydroxy-17a (Z-butynyl) -30t,50t-CyClOaIld1O- stan-6-one 17-isobutyrate (IV),

(2) 17fl-hydroxy-17a-chloroethynyl-3n h-cycloandrostan-6-one l7-valerate (IV), etc.,

yields, respectively,

(1) 17B-hydr0xy-17a (Z-butynyl)-7-methylene-3u,5a-

cycloandrostan 6-one 17-isobutyrate (V),

(2) 17B-hydroxy-17a-chloroethynyl-7-methylene-301,504-

cycloandrostan-6-one l7-valerate (V), etc.

PREPARATION 5 7 Following the procedure of Preparation 43 but substituting hydroxy 17a vinyl 19 nor 3a,5acycloandrostan-6-one (IV) (obtained in Preparation 19) as starting material, yields 17,8 hydroxy 17cc vinyl-7- methylene-19-nor-3a,5a-cycloandrostan-6-one (V).

Following the procedure of Preparation 57 but sub stituting other corresponding l7a-alkenyl compounds (IV) as starting materials, such as (1) 17fl-hydroxy-17a(3-penteny1)-19-nor-3 11,51:-

cycloandrostan-6-one (IV),

(2) 17 S-hydroxy-17a (4-nonenyl) -19-nor-3 11,5-

cycloandrostan-G-one (IV),

(3) 17fl-hydroxy-17a-trifiuoromethylvinyl-19-nor-3a,5 x-

cycloandrostan-6-one (IV),

(4) 17fi-hydroxy-17a(l-propenyl)-19-n0r-3a,5a-

cycloandrostan-6-one (IV),

(5) 17 3-hydroxy-17a (Z-butenyl) -19-nor3 ,5 a-

cycloandrostan-6-one (IV), etc.,

yields, respectively,

( 1 17/3-hydroxy-17a (3-pentenyl) -7-methylene-9-nor- 3a,5u-cycloandrostan-6-one (V),

(2) 17/3-hydroxy-17a(4-nonenyl)-7-methylene-19-nor- 3 01,5 a-cycloandrostan-6-one (V),

(3) 17fl-hydroxy-17a-trifluoromethylvinyl-7-methylene- 19-nor-3u,5u-cycloandrostan-6-one (V),

(4) 17,6-hydroXy-17a( l-propenyl) -7-methylene-19-nor- 3a,5et-cycloandrostan-6-one (V),

(5 17,6-hydroXy-17a (Z-butenyl) -7-methylene-19-nor- 3a,5a-cycloandrostan-6-one (V), etc.

PREPARATION 58 l 7 3-hydr0xy-1 7 a-vinyl-7 -methylene-3a,5acyclandr0stan-6-0ne (V) Following the procedure of Preparation 43 but substituting 17p hydroxy-17ot-vinyl-3a,5a-cyc1oandrostan-6- one (IV), (obtained in Preparation 30) as starting material, yields 17fi-hydroxy-17a-vinyl-7-methylene-3a,5acycloandrostan-6-one (V).

Following the procedure of Preparation 58 but substituting other corresponding 17a-alkenyl compounds (IV) as starting materials, such as (1 17fi-hydroXy-17a(1-propenyl)-3 01,5 a-cycloandrostam 6-one (IV),

(2) 17/3-hydroxy-17a-chlorovinyl-3a,5acycloandrostan- 6-one, etc.,

yields, respectively,

(1 17 B-hydroxy-l 7a( l-propenyl) -7-methylene-3 11,50:-

cycloandrostan-G-one (V),

(2) 17,8-hydroxy-17a-chlorovinyl-7-methylene-3u,5a-

cycloandrostan-6-one (V), etc.

PREPARATION 59 1 7fl-hydr0xy-1 7 a-vinyl-7-methylene-1 9-nor-3a,5acycl0andr0stan-6-0ne 1 7-ace1ate (V) Following the procedure of Preparation 43 but substituting 175 hydroxy 17oz vinyl-19-nor3a,5a-cycloandrostan-6-one 17-acetate (IV) (obtained in Preparation 41) as starting material, yields 17,3-hydroxy-17uvinyl-7-methylene-19-nor-3a,Sa-cycloandrostan-G-one 17- acetate (V).

Substituting other 17-acylates of 17fi-hydroxy-17a-vinyl- 19-nor-3a,5a-cycloandrostan-6-one (IV), such as the 17- propionate, 17-hexanoate, 17-decanoate, 17-phenylacetate, etc., for the 17-acetate compound employed as starting material in the preceding paraghaph, yields the corresponding 17B hydroxy-17a-vinyl-7-methylene-19-nor-3u, a-cycloandrostan-6-one 17-acylate (V).

Following the procedures of the immediately preceding paragraph and of Preparation 59 but substituting other representative corresponding 17a-alkenyl 17-acylates (IV), such as (1) 17 fl-hydroxy-lhQ-butenyl)-19-nor-3a,5 (Z- cycloandrostan-6-one 17-isobutyrate (IV),

(2) 17,8-hydroxy-17a (4-hexenyl -19-nor-3 o,5a-

cycloandrostan-6-one 17-phenylpropionate (IV), etc.,

yields, respectively,

( 1 17 3-hydroxy-17u(2-buteny1) -7-methylene-19-nor- 3a,5a-cycloandrostan-6-one 17-isobutyrate (V),

(2) l7B-hydroxy-17a (4-hexenyl)-7-methylene19-nor- 3u,5a-cycloandrostan-6-one 17-phenylpropionate (IV), etc.

PREPARATION 60 1 7 p-hydroxyJ 70t-vinyl-7-methylene-3a,5acycloandrostan-ti-one 17'-acetate (V) Following the procedure of Preparation 43 but substituting 17 3 hydroxy 17a vinyl-19-nor-3a,5a-cycloandrostan-6-one 17-acetate (IV) (obtained in Preparation 41) as starting material, yields 17fl-hydroxy-17avinyl 7-mehylene-3(1,5a-cycloandrostan-6-one 17-acetate (V).

Substituting other 17-acylates of 17fi-hydroXy-17a-vinyl- 3a,5a-cycloandrostan-6-one (V), such as the 17-propionate, 17-isobutyrate, l7-hexanoat e, 17-pheny1propionate, etc., for the 17-acetate employed as starting material in the preceding paragraph, yields the corresponding 17flhydroxy 17a vinyl-7-rnethylene-3a,5a-cycloandrostan-6- one l7-acylate (V). 1

Following the procedures of the immediately preceding paragraph and of Preparation 60 but substituting other representative corresponding 17a-alkenyl 17-acylates (IV), such as (1 17B-hydroxy-17a(2-pr0penyl) -3 a,5a-cycloandrostan- 6-one 17-valerate (IV),

( 2) 17 ,B-hydroxy-17 a 3 -hexenyl) -3 a,5 ot-cycloandrostan- 6-one 17-trimethylacetate (IV), etc.,

yields, respectively,

(1) l7Bhydroxy-17a(2-propenyl)-7-methylene-3a,5a-

cycloandrostan-6-one 17-valerate (V),

(2) 17fl-hydroxy-l 7a 3-hexenyl) -7-methylene-3a,5acycloandrostan-G-one 17-trimethylacetate (V), etc.

EXAMPLE 1 Spiro 6,1 7-di0x0-3 a,5a-cycloandrostane-Z3 [1 pyrazoline] VI) To a mixture of 15 ml. of 45% aqueous potassium hydroxide and ml. of ether cooled in an ice bath, 4 g. of N-methyl-N-nitroso-N-nitroguanidine (J. Amer. Chem. Soc. 69, 3-18) is added slowly in small portions. The thus produced diazomethane contained in the ether phase is decanted. To the diazomethane solution, 2 g. of 7-methylene-3a,5a-cycloandrostane-6,17-dione (V) (prepared as in Preparation 44) is added. After standing at room temperature for about 16 hours the solution is evaporated to dryness and the residue recrystallized from a mixture of acetone and Skellysolve B (hexanes) to give 1.85 g. of spiro[6,17-dioxo-3a,5a-cycloandrostane-7,3' [1]pyrazoline] (VI) melting at to C. with bubbling) and having a rotation (at) of -354 (chloroform). Its infrared absorption spectrum shows 17-C=O and 6C=O bands at 1740 and 1680 emfrespectively. The nuclear magnetic resonance (NMR) spectrum (CDCl of the compound (VI) shows: a .92 (C-18), 1.156 (C-19), 4.26 to 5.16 (multiplet pyrazoline CH Analysis.Calcd. for C H O N (percent): N, 8.23. Found (percent): N, 8.52.

Following the procedure of Example 1 but substituting other representative 7-methylene compounds (V) (obtained in Preparation 43 through 60) as starting materials, such as (1) 7-methylene-19-nor-3a,5a-cyc'loandrostane 6,17-dione (V),

(2) 17p-hydroxy-7-methylene-19-r1or-3u,5a-cycloandrostan-6-one 17-acetate (V),

(3) 17fi-hydroxy-7-methy1ene-3a,5a-cycloandrostan- 6-one (V),

(4) 17fi-hydroxy-7-methylene-3a,5u-cycloandrostan- 6-one 17-butyrate (V),

(6) 17,8-hydroxy-17ot-isopropyl-7-methylene-3a,5a-

cycloandrostan-6-one 17-valerate (V),

(7) 17,8-hydroxy-17u-ethynyl-7-methylene-19-nor- 3a,5a-cycloandrostan-6-one (V),

( 8 17 fi-hydroxy- 17 a-trifiuoromethylethynyl-7-methylene-3 a,5a-cycloandrostan-6-one (V),

(9) 17fi-hydroxy-17a(Z-butynyl)-7-methylene-19-nor- 3a,5a-cycloandrostan-6-one 17-phenylacetate (V),

( 10) 17,B-hydroxy-17a( l-propynyl) -7-II1ethylIl@-3OL,5(X-

cycloandrostan-6-one 17-va1erate (V),

( 11) 17fi-hydroxy-17a-vinyl-7-methylene-19-nor-3a,5a,

cycloandrostan-6-one (V),

(12) 17 B-hydroxy-17 a l-propenyl) -7-methylene-3u,5 u-

cycloandrostan-6-one (V),

(13) 17fl-hydroxy-17a(2-butenyl)-7-methylene-19-nor- 3a,5u-cycloandrostan-6-one 17-trimethylacetate (V),

(14) 17,8-hydroxy-17u-hexenyl-7-methylene-3a,5acycloandrostan-6-one 17-propionate (V), etc.,

yields, respectively,

( 1) spiro[6,17-dioxo-19-nor-3a,Sat-cycloandrostane- 7,3 '-[1]pyrazoline] (VI),

(2) spiro[ 17 ,B-hydroxy-6-oxo- 19-nor-3 a,5a-cycloandrostane-7,3'-[1]pyrazoline] 17-acetate (VI),

(3) spiro[17B-hydroxy-6-oxo-3a,5a-cycloandrostane- 7,3 '-[1]pyrazoline] (VI),

(4) spiro[17fi-hydroxy-6-oxo-3a,5a-cycloandrostane- 7,3-[1]pyrazoline] 17-butyrate (VI),

( 5) spiro[ 17,8-hydroxy-17a-methyl-6-oxo-19-nor-3a,5a-

cycloandrostane-7,3 1]pyrazoline] (VI (6) spiro[17/3-hydroxy-17a-isopropyl-6-oxo-3a,5otcycloandrostane-7,3 1 ]pyrazoline] 17-valerate (7) spiro[17fi-hydroxy-17a-ethynyl-6-oxo-19-nor-3 :,5oc-

cycloandrostane-7,3 '-[1 ]pyrazoline] (VI),

(8) spiro[ 17/3-hydroxy-17a-trifluoromethyl-ethynyl- 6-oxo-3a,5 a-cyc1oandrostane-7 ,3 '-[1]pyrazoline] (V 9) spiro[ 17fl-hydroxy-17a(2-butynyl-6-oxo-19-nor- 3a,5a-cycloandrostane-7,3 '-[1]pyrazoline] 17- phenylacetate (VI),

( 10) spiro[17B-hydroxy-17a(l-propynyl-6-oxo)-3 (1,50;-

cycloandrostane-7,3 1 ]pyrazoline] 17-valerate (11) spiro[17 8-hydroxy-17a-vinyl-6-oxo-19-nor-3a,5a-

cycloandrostane-7,3'-[1]pyrazoline] (VI),

( 12) spiro[ 17B-hydroxy-17a( 1-propenyl)-6-oxo-3 11,504-

cycloandrostane-7 ,3 -[1]pyrazoline] (VI),

( 13) spiro[17fl-hydroxy-17a(2-butenyl)-6-oxo-19-nor- 3a,5a-cycloandrostane-7,3 '-[1]pyrazoline] 17- trimethylacetate (VI),

( 14) spiro 17p-hydroxy- 1 7a-hexenyl-6-oxo-3a,5a-

cycloandrostane7,3 [1]pyrazoline] 17- propionate (VI), etc.

EXAMPLE 2 7-spir0cycl0pr0pyl-3a,5a-cycloandrostane-6,1 7

dione VII) 7-ethylidene-3u,5a-cycl0andr0stane-6,1 7 -di0ne (Vlla) 7- (2 -hydroxyethyl -3a,5u-cycl0andr0stane-6,1 7 dione (VIIb) 1.5 g. of spiro[6,17 dioxo-3a,5a-cycloandrostane- 7,3'-[1]pyrazoline] (VI) (obtained in Example 1) is heated in a Woods metal bath at about 150 C. under vacuum until bubbling ceases. The product is chromatographed through a silica gel (silicic acid) column. The non-polar fractions are combined and rechromatographed through a 150 g. column of Florisil (synthetic magnesium silicate) packed wet with Skellysolve B (hexanes); separation is carried out by gradient elution with 400 ml. fractions between l. of Skellysolve B (hexanes) and 5 l. of a mixture containing acetone and Skellysolve B (hexanes). Those fractions exhibiting u.v. absorption near 244 m (fractions 19 through 24) are combined and recrystallized from acetone-Skellysolve B (hexanes) to give 480 mg. of 7-ethylidene-3a,5a-cyc1oandrostane-6,17- dione (VIIa), having a melting point of 160 to 161 C.; A ale. max. 244 m (e=9,950); [a] -|l81 (chloroform); infrared spectrum having absorption maxima at 1730, 1665 and 1600 cm.- nuclear magnetic resonance (NMR) spectrum (CDCl 60.98 (C-18), 1.02 (C-19), 1.92 (doublet of doublets J=7 c.p.s. and 1.5 c.p.s. =CHCI 5.82 (double quartet 1:7, 0.5 c.p.s., =CH-CH Decoupling experiments show 1.91 and 5.82 systems are coupled; mass spectrum: M/e 312, 297, 284, 279, 269.

Those fractions with IR absorption at 1735 and 1660 cm.- with no OH absorption (fractions 26 through 32) are combined and recrystallized from a mixture of acetone and Skellysolve B to give 0.34 g. of 7-spirocyclopropyl 304,504 cycloandrostane) 6,17 dione (VII), melting at 189 to 192 C.; [u] +131 (chloroform); infrared spectrum showing absorption maxima at 1735 and 1660 cmr NMR spectrum (CHCl 50.9 (C-18), 1.05 (C-9), small bands observed in the 0.7-0.8 region are assigned to the cyclopropyl group; mass spectrum: M/e 312, 297,187.

The more polar crystalline fractions of the silica gel column are combined and recrystallized from acetone- Skellysolve B to give mg. of 7-(2'-hydroxyethyl)- 3a,5a-cycloandrostane-6,17-dione (VIIb); melting point 138 to 142 C. (with decomposition); infrared spectrum shows absorption maxima at 3460 (OH). 1735 (C=O), 1665 cm. ((3 0) NMR spectrum (CDCl 50.92 (C-18), 1.04 (C-19), 3.3 (broad OH), 3.75 (t, J=5.5 c.p.s. =Cg OH); mass spectrum: M/e 330, 312.

Heating a mineral oil suspension of spiro (6,17-dioxo)- 3a,5u-cycloandrostane 7,3 [l]pyrazoline] (VI) at to C. also gives 7-spirocyclopropyl-3a,5a-cycloandrostane-6,17-dione (VII).

Following the procedure of Example 2 but substituting other representative pyrazoline compounds (VI) as starting materials, such as (1 spiro[6,17-dioxo-19 nor-3a,5a-cycloandrostane- 7,3-[1]pyrazoline] (VI) (2) spiro[17;i-hydroxy-6-oxo-3 u,5u-cycloandrostane- 7,3 '-[1]pyrazoline] (VI),

(3 spiro[17,8-hydroxy-17a-isopropyl-6-oxo-3 04,5 a-

cycloandrostane-7,3'-[1]pyrazoline] 17-acetate (V (4) spiro[ l7 3-hydroxy-17a-ethyny1-6-oxo-19-nor-3a,5a-

cycloandrostane-7,3 -[1]pyrazoline] (VI),

(5) spiro[17fi-hydroxy-17a(1-propynyl)-6-oxo-3 a,5ot-

cycloandrostane-7,3-[1]pyrazoline] 17-valerate (V (6) spiro 17 fl-hydroxy-17-viny1-6-oxo-3 oc,5u cycloandrostane-7,3 '-[1]pyrazoline] (VI) (7 spiro[17B-hydroxy-17a(2-butenyl)-6-oxo-19-nor 3 a, 504 cycloandrostane-7,3 '-[1]pyrazoline] (VI) etc.,

yields, respectively,

(1) 7-spirocyclopropyl-19-nor 3u,5u-cycloandrostane 6,

17-dione (VII); 7-ethylidene-19-nor-3a,5u-cycloandrostane-6,17-dione (VIIa); 7-(2'-hydroxyethyl)-19 nor- 3 a,5a.-cycloandrostane-6,17-dione (VIIb (2) -hydroxy-7-spirocyclopropyl-311,50; cycloandrostan-6-0ne (VII); 1'7fi-hydroxy-7-ethylidene-3a,5a-cycloandrostan-6-one (VIIa); 17/8-hydroxy-7-(2'-hydroxyethyl) -3 0;,5 u-cycloandrostan-6-one (VIIb (3) 17B-hydroxy-17a-isopropyl-7-spirocyc1opropyl-3a,5acycloandrostan-6-one 17-acetate (VII); 17,8-hydroxy- 17a isopropyl 7 ethylidene-3a,5or-cycloandrostan-6- one 17-acetate (VIIa); 17/3-hydroxy-l7a-isopropyl-7- (2-hydroxyethyl)-311,5a-cycloandrostan-6-one 17-acetate (VIIb),

(4) 17fi-hydroxy-l7a-ethynyl-7-spirocyclopropyl-19 nor- 3a,5a-cycloandrostan-6-one (VII); 17fi-hydroxy-17a- EXAMPLE 3 To a solution of 0.27 g. of 7-spirocyc1opropyl-304,50- cycloandrostane-6,l7-dione (VII) (obtained in Example 2) in 10 ml. of methanol, an excess (0.1 g.) of sodium borohydride is added while cooling the reaction mixture in an ice bath. Crystals form as the solution cools. After the crystals dissolve, water is added and, the precipitated product is collected. The product is recrystallized twice from acetone-Skellysolve B to give 7-spirocyclopropyl3a, a-cycloandrostane-6oc,17/3-di0l (VIII) with a melting point of 170 to 172 C.; [a] +40 (dioxane); infrared spectrum having absorption maxima at 3450, 3410 cm.

Analysis.-Calcd. for C H O (percent): C, 79.70; H, 10.19. Found (percent): C, 79.25; H, 9.90.

Following the procedure of Example 3 but substituting other representative 6-keto compounds (VII) as starting materials, such as (l) 7-spirocyclopropyl-19-nor-3a,5a-cycloandrostane 6,

17-dione (VII),

(2) 171i-hydroxy-7-spirocyclopropyl-30;,50; cycloandrostan-6-one (VII),

(3) 17,6-hydroxy-17a-methyl-7-spirocyclopropyl-19 nor- 3a,5a-cycloandrostan-6-one 17-propionate (VII),

(4) l7a-ethynyl-7-spirocyclopropyl 30,5oz cycloandrocycloandrostan-6-one (VII),

(5) 17fi-hydroxy-17a(l-butynyl)-7-spirocyclopropyl 19- nor 304,50 cycloandrostan-6-one 17-trimethylacetate (6) 17,8-hydroxy-17a(l-propenyl)-7-spirocycloproyl 3oz,

5a-cycloandrostan-6-one (VII),

(7) 17/3-hydroxy-17w(1-butenyl)-7-cyclopropyl-l9 nor- 3m,5a-cycloandrostan 6-one 17-isobutyrate (VII), etc.,

yields, respectively,

(1) 7-spirocyclopropyl-19-nor 30,5oc cycloandrostane- 60:,17/3-di0l (V111),

(2) 7-spirocyclopropy1-3a,5a cycloandrostane 604,175-

diol (VIII),

(3) 17m-methyl-7-spirocyclopropyl-l9-nor 3a,5a cycloandrostane-6a,17fi-diol 17-propionate (VIII),

(4) 17a-ethynyl-7-spirocyclopropyl 301,50; cycloandrostane-6a,17;3-diol (VIII),

(5) 17a(Z-butynyl)-7-spirocyclopropyl-l9-nor-3a,5a cycloandrostane-6a,17fl-diol 17-trimethylacetate (VIII),

(6) l7u(l-propenyl)-7-spirocyclopropyl-3o Su cycloandrostane-6a,l7fi-diol (VIII), (7) 17oc( l-butenyl)-7-spirocyclopropyl-19-nor-3u,5u cycloandrostane-6u,17,3-dio1 17-isobutyrate (VIII), etc.

EXAMPLE 4 1 7 ,B-hydroxy-7-spirocycl0propyl-3 11,5 0!.- cycloandrostan-6-one (VII) To a solution of 1 g. of lithium aluminum tri-t-butoxyhydride in 15 ml. of tetrahydrofuran, 1 g. of 7-spirocyclopropyl-3a,5a cycloandrostane-6,l7dione (VII) (obtained in Example 2) is added with stirring at 0 C. The suspension is allowed to warm to room temperature during about 30 minutes, then dilute hydrochloric acid is added dropwise until all of the excess hydride is consumed. The solution is diluted with 15 ml. of water and the tetrahydrofuran removed under reduced pressure. The product is extracted into ether and the combined extracts Washed successively with water, saturated aqueous sodium chloride solution, dried with sodium sulfate and the solution evaporated to dryness under reduced pressure. The residue is recrystallized twice from a mixture of acetone and Skellysolve -B to yield 17,B-hydroxy-7-spirocyclopropyl- 3a,SwcyclOandrOstane-G-One (VII).

Following the procedure of Example 4 but substituting 7 spirocyclopropyl 19-I'l0r-301.,5oz-CYCIO81'1dIOSt2lI1C-6,17- dione (VII) as starting material, yields 17/3-hydroxy-7- spirocyclopropyl 19 nor 3u,5a-cycloandrostan-6-one (VII).

EXAMPLE 5 1 7 p-hydr0xy-7-spir0cyclopropy [-3 a,5 occycl0andr0stane 6-0ne (VII) A solution of 28.6 mg. of 7-spirocyclopropyl-3 5- cycloandrostane-6,17-dione (VII) and 1.3 mg. of sodium borohydride in 10 ml. of absolute ethanol is kept at room temperature for about 6 hours. Water is added to precipitate the product. The cottony crystals are collected and washed with water to give -hydroXy-7-spirocyclopropyl-3a,5a-cycloandrostan-6-one (VII) having a melting point of 181 to 184 C. Its structure is confirmed by its infrared spectrum which shows absorption bands at 3250 cm? (OH) and 1670 cm? (NC=O).

Following the procedure of Example 5 but substituting 7 spirocyclopropyl-19-nod-3u,5a-cycloandrostane-6,17- dione (VII) as starting material, yields 17B-hydroxy-7- spirocyclopropyl 19 nor 3a,5a-cycloandrostan-6-one (VII).

EXAMPLE 6 7 -spir0cycIopr0pyZ-3 04,5 a-cycloandrostan 6-6oz,1 718- dz'ol 6,17-diacetate- (VIII) A solution of 50 mg. of 7-spirocyclopropyl-311,50:- cycloandrostane'6a,l7fi-diol (VIII) (obtained in Example 3) in 10 drops of pyridine and 10 drops of acetic anhydride is kept at room temperature for about 20 hours. Water is added and the crude product extracted with ether, washed first with dilute hydrochloric acid and then sodium carbonate solution, dried with magnesium sulfate and evaporated to dryness to yield 7-spirocyclopropyl 3a,5a-cycloandrostane-6az,17/8-diol 6,17-diacetate (VIII). The product resists crystallization. Its thin layer chromatographic analysis shows only one spot and its infrared spectrum shows C=O absorption at 1740 cm.- and C0 at 1240 CHI-"1.

NMR (CD1 6 0.20 (m-cyclopropyl-H), 0.82 (S,C18), 1.07 (S,C-l9), 1.92 (S,CH CO), 2.01 (S,CH 4.53 mm-H), 5.42 (S,6p-H).

Similarly, by reacting 7-spirocyclopropyl-3mafia-cycloandrostane-6a,17,8-diol (VIII) with the appropriate hydrocarbon carboxylic acid anhydride (instead of acetic anhydride) and using the procedure of Example 6, there are produced other 6,17-diacylates thereof, such as the 6,17-dipropionate, 6,17-dibutyrate, 6,17-divalerate, 6,17- dihexanoate, 6,17-ditrimethylacetate, 6,17-diisobutyrate, 6,17-diphenylpropionate, 6,17-diacrylate, 6,17-dicinuamate, 6,17-diundecylenate, 6,17-dipropiolate, etc.

Following the procedures of the immediately preceding paragraph and of Example 6 but substituting other 31 representative 6u,17fl-diols (VIII) as starting materials and appropriate hydrocarbon carboxylic acid anhydrides, such as l 7-spirocyclopropyl-19-nor-3a,5a-cycloandrostane- 6oz,17[3di01 (VIII) and butyric anhydride,

(2) l7ot-ethyl-7-spirocyclopropyl-3a,5a-cyclodrostane- 6u,-l7B-di0l (VIII) and phenylpropionic anhydride,

(3 17 a (2-propnyl) -7-spirocyclopropyll9-nor-3a,5acycloandrostane-6u,17fl-diol (VIII), and cinnamic anhydride,

(4) 17a-vinyl-7-spirocyclopropyl-3a,5a-cycloandrostane- 6a,l7 3-diol (VIII) and acrylic anhydride, etc.,

yield, respectively,

1) 7 -spirocyclopropyl-l9-nor-3a,5 ot-cycloandrostane- 6u,l7fl-diol 6,17-dibutyrate (VIII),

(2) 17a-ethyl-7-spirocyclopropyl-3a,5a-cyclodrostane- 6a,17B-diol 6,17-diphenylpropionate (VIII),

(3) 17oz (2-propenyl) -7-spirocyclopropyl- 19-110r-3ec,5oz

cycloandrostane-6u,l7B-diol 6,17-dicinnamate (VIII),

(4) 17u-vinyl-7-spirocyclopropyl-3a,5a-cycloandrostane- 6u,l7 3-diol 6,17-diacrylate ,(VIII) etc.

EXAMPLE 7 7 -spircycl0propyl-3 11,5 u-cycl0androsrane-6 04,1 7,8- diol 17-acetate (VIII) Following the procedure of Example 3 but substituting 17;? hydroxy-7-spirocyclopropyl-3u,5a-androstan-6- one l7-acetate (VII) as starting material, yields 7-spirocyclopropyl-3a, 50c cycloandrostane 6a,17[3-di01 17-acetate (VIII).

Following the procedure of Example 7 but substituting other representative 6-keto compounds (VII) as starting materials, such as l 17 B-hydroxyl7a-propyl-7-spirocyclopropyl- 19-nor- 3a,5a-cycloandrostan-6-one 17-propionate (VII),

(2) 17,8-hydroxy-l7ot-ethynyl-7-spirocyclopropyl-3a,5acycloandrostane-6-one 17-trimethylacetate (VII),

(3 17/3-hydroXy-17a (Z-pentenyl -7-spirocyclopropyl- 19-nor-3a,5a-cycloandrostan-6-one 17-isovalerate (VII),

etc., yields, respectively,

(1) 17u-propyl-7-spirocyclopropyl-l9-nor-3a,5a-

cycloandrostane-6u, l7B-diol l7-propionate (VIII),

(2) l7u-ethynyl-7-spirocyclopropyl-3aim-cycloandrostanel6a,l7B-diol 17-trimethylacetate (VIII),

(3 17a (Z-pentenyl -7-spirocyclopropyll 9-nor-3 a,5oc-

cycloandrostane-6a,l7fl-diol l7-isovalerate (VIII), etc.

EXAMPLE 8 7-spir0cyclopr0pyl-3a,5a-cycl0andr0stane-6,17- di0ne-17-ketal EXAMPLE 9 3a,5a-cyclospir0 [andr0stane-7,1 -cyclopr0pane] -6a- 01-1 7-one 1 7-ketal To a solution of 0.25 g. of 7-spirocyclopropyl-304,504- cycloandrostane-6,17-dione l7-ketal in 10 ml. of methanol, 0.10 g. of sodium borohydride is added at room temperature. After 1 hour, water is added and the precipitated product is collected. The product is recrystallized from acetone and Skellysolve B to give 6ot-hydroXy-7-spirocyclopropyl-3a,5ot-cycloandrostan-l7-one 17-ketal.

Following the procedure of Example 9 but substituting 7 spirocyclopropyl l9-nor-3a,5a-cycloandrostane-6,l7- dione 17-ketal as starting material, yields 6a-hydroxy-7- spirocyclopropyl-l9-nor-3u,5u-cycloandrostan-17-one 17- ketal.

EXAMPLE 10 6 a-hydroxy-7 -spirocyclopr0pyl-3 04,5 a-cycloandrostan 17-one (VIII) To a solution of 1.0 g. of 6u-hydroXy-7-spirocyclopropyl-3u,5u-cycloandrostan-l7-one l7-ketal (obtained as in Example 9) in 20 ml. of acetone, 0.10 g. of ptoluenesulfonic acid is added and the reaction mixture allowed to remain at room temperature for about 10 hours. Addition of water to the reaction mixtures precipitates the crude product (VIII) which is recovered by filtration. Three recrystallizations of this material from methanol yields pure 6tat-hydroxy-7-spirocyclopropyl- 3u,5a-cycloandrostan-l7-one (VIII).

Following the procedure of Example 10 but substituting 6a hydroxy 7 spirocyclopropyl 19Il0l-30c,5ot-CYC1O androstan-17-one 17-ketal as starting material, yields 60c hydroxy 7 spirocyclopropyl-19-nor-3u,5a-cycloandrostane-l7-one (VIII).

EXAMPLE 11 6a-hydroxy-7-spirocyclopropyl-3a,5u-cycl0andr0stan- 17-0ne 6-acetate (VIII) A solution of l g. of 6a-hydroxy-7-spirocyclopropyl- 3a,5a-cycloandrostan-17-one (VIII) (obtained as in EX- ample lO) in 1 ml. of acetic anhydride and 2 ml. of pyridine is stirred for about 72 hours at room temperature. Water is then slowly added to the reaction mixture and the product extracted with methylene chloride, washed with aqueous sodium carbonate solution until nearly neutral, dried and the solvent removed under vacuum. The residue is chromatoglraphed through a column of Florisil to give 6a-hydroXy-7-spirocyclopropyl- 3a,5a-cycloandrostan-l7-one 6-acetate (VIII).

Following the procedure of Example 11 but substituting Got-hydroxy 7-spirocyclopropyl-l9-nor-3a,5a-cycloandrostan-17-one (VIII) as starting material, yields 6ahydroxy 7 spirocyclopropyl-19-nor-3a,5u cycloandrostan-l7-one G-acetate (VIII).

Similarly, reacting 6a-hydroxy-7-spirocyclopropyl-3a, 5a-cycloandrostan-17-one (VIII) or its l9-nor-counterpart (VIII) with the appropriate hydrocarbon carboXylic acid anhydride (instead of acetic anhydride) and using the procedure of Example 11, there are produced other 6-acylates thereof, such as the 6-propionate, 6-hexanoate, 6-phenylpropionate, G-decylenate, 6-propiolate, etc.

By following the procedure of the immediately preceding paragraph but substituting a hydrocarbon carboxylic acid halide for a hydrocarbon carboxylic acid anhydride, such as acetyl chloride, phenylpropionyl chloride, capryl bromide, etc., there are produced 6-acylates of 6a hydroxy 7 spirocyclopropyl-3a,5a-cycloandrostan-l7-one (VIII) or its l9-nor-counterpart, such as the 6-acetate, 6-phenylpropionate, 6-caprylate, etc.

EXAMPLE l2 7-spz'rocycl0pr0pyl-5 androstene-35,1 7/3-diol (IX) To a solution of 300 mg. of 7-spirocyclopropyl-311,50:- cycloandrostane-6a,l7B-diol (VIII) (obtained as in EX- ample 3) in 2 ml. of tetrahydrofuran, 4 drops of water and 4 drops 70% perchloric acid is added with cooling in a cold water bath. After about 10 minutes the product is precipitated by adding water. The product is filtered and recrystallized twice from ethyl acetate to give mg. of pure 7-spirocyclopropyl-5 androstene 313,17p-diol, having a melting point of 224 to 229 C. and [ab-106 (dioxane).

NMR (dimethylsulfoxide) .20 (S,cyclopropyl H), 0.62 (S,C18), 1.0 (S,C19), 3.37(m,3 and 17-H), 4.41 (S,6-H).

Analysis.-Calcd. for C H O (percent): C, 79.70; H, 10.19. Found (percent): C, 79.34; H, 10.57.

Following the procedure of Example 12 but substituting other representative compounds of Formula VIII, such as 1) 7-spirocyclopropyl-19-nor-3a,5ot-cycloandrostane- 60,17B-d101 (VIII),

(2) 17a-propyl-7-s-pirocyclopropyl-3u,5ot-cycloandrostane-6a,17fi-diol (VIII),

(3) 17a(1-butyny1)-7-spirocyclopropyl-19-nor-3a,5u-

cycloaridrostane-6a,17 3-diol (VIII),

(4) 17a-bromoethynyl-7-spirocyclopropyl-3mafia-cycloandrostane-6a,17fi-diol (VIII) (5) 17a (3pentenyl) -7-spirocyclopropyl-l9-nor-3a504- cycloandrostane-6a,17,8-dio1 (VIII),

(6) 6a-hydroxy-7-spirocyclopropyl-3cadet-cycloandrostan-17-one (VIII), etc.,

yields, respectively,

( 1 19-nor-7-spirocyclopropyl-Sandrostene-3fl, 17 B- diol (IX),

(2) 17u-propyl-7-spirocyclopropyl-S-androstene-3/8,

17p-dio1 (IX),

(3) 17a l-butynyl -19-nor-7-spirocyclopropyl-S- androstene-3 [1,l7B-diol (IX),

(4) 17a-bromoethynyl-7-spirocyclopropyl-5-androstene- 35,175-diol (IX),

(5) 17a(3-pentenyl) -19-nor-7-spirocyclopropyl-5- androstene-3/3,17/3-diol ('IX) (6) 3l3-hydroxy-7-spirocyclopropyl-S-androsten-17-one (IX), etc.

EXAMPLE 13 7-spir0cyclopr0p-yl-5-andr0sterte-35,1 75-11 1' 0l 17-acezate (IX) To a solution of 10 mg. of 7-spirocyclopropyl-3afloacycloandrostan-6rx,17B-diol 6,17 diacetate (VIII) (obtained as in Example 6) in 0.5 ml. of acetone, 0.05 .ml. of 1.1 N perchloric acid is added. After about 1 hour water is added to crystallize the product. It is collected, washed with water, dried and crystallized from aqueous acetone to yield 7-spirocyclopropyl-5-androstene-3B,17,8- diol 17-acetate (IX), M.P. 170 to 171 C., infrared spectrum 3800, 1720, 1250, 1270 and 1050 CHI-*1. If desired, chromatography is used for purification in addition to crystallization.

Following the procedure of Example 13 but substituting another 6,17-diacylate of a compound of Formula VIII, such as (1 7-spirocyclopropyl-19-nor-3a,Sa-cycloandrostane- 6u,17fl-diol 6,17-div-a1erate (VIII),

(3) 17a-butyny1-7-spirocyclopropyl-19-nor-3 ot,5oc-CYC10- androstane-6a,17,B-diol 6,17-ditrimethylacetate (VIII),

(4) 17u-vinyl-7-spirocyclopropyl-3a,5oc-cycloandrostane- 60,17fl-di01 6,17-dipropiolate (VIII), etc.,

yields, respectively,

( 1) 7-spirocyclopropyl-19-nor-5-androstene-3 3,17 3-diol 17-valerate (DO,

(2) 17vt-butyl-7-spirocyclopropyl-5-androstene-3 3,175-

diol 17-hexanoate (IX),

(3) 17ocl-butynyl)-7-spirocyclopropyl-19-nor-5-androstene-3 6,17,8-diol l7-trirnethylacetate (VIII),

(4) 17ot-vinyl-7-spirocyclopropyl-5-androstene-33,1713- diol l7-propiolate ('IX), etc.

EXAMPLE 14 7 -spir0cycl0pr0pyl-5-androstene-3 5,1 7 B-diol 3-p-toluenesulf0nate A solution of 0.1 g. of 7 spirocyclopropyl-S-androstene-3,8,l7p-diol (IX) (obtained in Example 12) and 0.07 g. of p-toluenesulfonyl chloride in 1 ml. of pyridine is kept at 5 C. for about 24 hours and then at room temperature for about 24 hours. Water is added to precipitate the product, which is then collected, washed with water, dried and recrystallized from a mixture of acetone and Skellysolve B to yield 7 spirocyclopropyl-S-androstene-3 [3,17fl-diol 3-p-toluenesulfonate.

Following the procedure of Example 14 but substituting 7 spirocyclopropyl-l9-nor-5-androstene-3/3,17fi-dio1 (IX) for 7-spirocyclopropyl-5-androstene 35,17/3-dio1 (IX) yields 7-spirocyclopropyl 19 nor-S-androstene- 35,17fl-diol 3-p-toluenesulfonate.

EXAMPLE 14A 7-spir0cycl0pr0 pyl-5 -androstene-3 ,8,1 7 ,B-diol 17-acetale 3-p-t0luenesulf0nate 1 3e-hydroxy-7-spirocyclopropyl-5-androsten-17-one (2) 17u-methyl-7-spirocyclopropan-19-nor-5-androstene- 35,17p-diol (IX),

(3 17 a-ethynyl-7-spirocyclopropy1- 19-nor-5 -androstene- 3,8,l7fl-diol 17-acetate (IX),

(4) 17a-trifluoromethylethynyl-7-spirocyclopropyl-l9- nor-5-androstene-3B,17[5-dio1 (IX),

(5) 17a l-propenyl -7 -spirocyc1opropyl-5 -androstene- 3,8,17,8-diol l7-valerate (IX), etc.,

yields, respectively,

( l) 3fl-hydroxy-7-spirocyclopropyll-S-androsten-17-one 3-p-toluenesulfonate,

(2) 17a-methyl-7-spirocyclopropyl-19-nor-S-androstene- 3 5,175-diol 3-p-toluenesulfonate,

(3) 17u-ethynyl-7-spirocyclopropyl-19-nor-5-androsten- 36,17fl-diol 17-acetate 3Bp-toluenesulfonate,

(4) l7a-trifluoromethylethynyl 7 spirocyclopropyl-1(9- nor-5-androstene-3fi,17B-diol 3-p-toluenesulfonate,

(5 17a( l-propenyl)-7-spirocyclopropyl-5-androstene- 35,17,6-dio1 17-valerate 3-p-to1uenesulfonate, etc.

EXAMPLE 15' A solution of 0.1 g. of 7-spirocyc-lopropyl-S-androstene- 35,17,8-di0l 3Bp-toluenesulfonate (obtained as in Example 14), 0.3 g. of potassium acetate and 10 ml. of methanol is heated at reflux temperature for about 6 hours, then 10 ml. of water is added and the methanol evaporated under a stream of nitrogen. The reaction mixture is extracted with methylene chloride and the extract Washed with saturated aqueous sodium chloride, dried over sodium sulfate, and evaporated to dryness. The residue is chromatographed over silica gel to give 6 6-meth0xy-7- spirocyclopropyl-3a,5a-cycloandrostan-17fi-ol (VIII).

Following the procedure of Example 15 but substituting for 7-spirocyclopropy1-S-androstene-3,8,17,8-dio1 3-p-toluenesulfonate and methanol, other starting materials and other alkanols, such as yields, respectively,

( 1) 6 3-ethoxy-7-spirocyclopropyl-3u,5a-cycloandrostan- 17-0ne (VIII),

(2) 6B-propoxy-7-spirocyclopropyl-19-nor-3a,5o-cyc1oandrostan-l7 8-ol 17-acetate (VIII),

(3) 6fi-isobutoxy-17a-heptyl-7-spirocyclopropyl-19-nor- 3a,5a-cycloandrostan-17,6-01 (VIII),

(4) 6fi-pentoxy-17a(3-butynyl)-7-spirocyclopropyl-3a,

5a-cycloandrostan-17fi-0l 17-priopionate (VIII),

(5) 6}3-heptoxy-17a-bromoethynyl7-spirocyclopropyl- 1'9-nor-3a,5u-cycloandrostan-176-01 (VIII) (6) 6B-decanoxy-17a( l-propenyl) -7-spirocyclopropyl- 3u,5a-cycloandrostan-1718-01 17-isovalerate (VIII), etc.

EXAMPLE 16 A solution of 0.3 g. of potassium acetate in 7 ml. of water and 7 ml. of acetone is purged with nitrogen and 0.1 g. of 7-spirocyclopropyI-S-androstcnc-3,8,17B-diol 3- p-toluenesulfonate (obtained as in Example 14) added. The mixture is heated at reflux temperature for about 6 hours and the acetone is then evaporated with a fast stream of nitrogen. The residual product (VIII) is chromatographed through a column of silica gel (silicic acid) to give 7-spirocyclopropyl-3a,5a-cycloandrostane-6/3,l7j8- diol (VIII).

Following the procedure of Example 16 but substituting for 7-spirocyclopropyl-S-androstene-3B,17B-diol 3-p-toluenesulfonate, other A starting materials, such as l 3 ,8-hydroxy-7-spirocyclopropyl-l9-nor-5-androsten- 17-one 3-p-toluenesulfonate,

(2) 7-spirocyclopropyl-19-nor-5-androstene-3fl,17fl-diol 17-butyrate 3-p-toluenesulfonate,

(3 l7a-methyl-7-spirocyclopropyl-5-androstene-3/3,17,8-

diol 3-p-toluenesulfonate,

(4) 17a-ethynyl-7-spirocyclopropyl-19-nor-5-androstene- 35,17fi-dio1 3-p-toluenesulfonate,

(5) -17a-methy1-7-spirocyclopropyl-5-androstene-3 5,176-

diol 3-p-toluenesulfonate,

(6) 17a( l-pentenyl) -7-spirocyclopropyl-19-nor-5-androstene-3,8,l7/3-diol l7-propionate 3-p-toluenesulfonate, etc.,

yields, respectively,

( 1 6fl-hydroxy-7-spirocyclopropyl-19-nor-3a,5a-cycloandrostan-17-one (VIII),

(2) 7-spirocyclopropyl-19-nor-3a,5a-cycloandrostane- 6,8,17,6-diol 17-butyrate (VIII),

(3) 17a-ethynyl-7-spirocyclopropyl-3a,5u-cycloandrostane-6;8,1713-diol (VIII),

(4) l7a-ethynyl-7-spirocyclopropyl-19-nor-3a,5a-cycloandrostane-6/3,17;8-diol (VIII),

(5) 17a-methyl-7-spirocycl0propyl-3a,5a-cycloandrostane-6/8,l7fi-di0l (VHI),

(6) 17a( l-pentynyl)-7-spirocycl0propyll 9-I1OF-3a,5ot-

cycloandrostane-QBA7fi-diol 17-priopinate (VIII), etc.

36 EXAMPLE 17 7-spirocycl0propyl-3a,5a-cycl0andr0stane- 6fl,l 7B-di0l 6,1 7-diacetate (VII) A solution of 250 mg. of 7-spirocyclopropyl-3a,5acycloandrostane-6fi,17fi-diol (VIII) (obtained as in Example 16) in 1 ml. of pyridine and 015 ml. of acetic anhydride is heated at about 80 C. for about 16 hours. Water is added to the reaction mixture and the crude product extracted with ether, the extract Washed first with dilute hydrochloric acid, then sodium carbonate solution, dried with magnesium sulfate and evaporated to dryness. Chromatography of the residue through Florisil and crystallization from acetone-Skellysol-ve B gives 7-spirocyclopropylda,5a-cycloandrostane-6/3,l7 8-diol 6,17 diacetate (VII Similarly, by reacting 7-spirocyolopropyl-3aim-cycloandrostane-6B,l7B-di0l (VH1) with the appropriate hydrocarbon carboxylic acid anhydride (instead of acetic anhydride) and using the procedure of Example 17, there are produced other 6,17-diacylates thereof, such as the 6,17-dibutyrate, 6,17-diheptanoate, 6,17-diphenylpropionate, 6,17-dipropyiolate, etc.

Following the procedures of the immediately preceding paragraph and of Example 17 but substituting other representative 6B,l7fi-diols (VIII) as starting materials and appropriate hydrocarbon carboxylic acid anhydrides, such as (1) 7-spirocyclopropyl-19-nor-3a,5 a-cycloandrostane- 65,17,8-diol (VIII) and propionic anhydride,

(2) l7a-isobutyl-7-spirocyclopropyl-3a,5ot-cycloandrostane-6B,17B-diol (VIII) and trimethylacetic anhydride,

(3) l7a-ethynyl-7-spirocyclopropyl-19-n0r-3a,5ot-cycloandrostane-6,8,17B-dio1 (VIII) and phenylpropionic anhydride,

(4) l7a-methyl-7-spirocyclopropyl-3a,5a-cycloandrostane-6/8,17fl-diol (VIII) and isovaleric anhydride, etc.,

yields, respectively,

(1) 7-spirocyclopropyl-19-nor-3a,5a-cycloandrostane- 6,8,175-di0l 6,17-dipropionate (VIII),

(2) 17a-is0butyl-7-spirocyclopr0pyl-3a,5ot-cycloandro- Mane-6,8, l7B-diol 6,17-ditrimethylacetate (VIII),

(3) 17wethynyl-7-spir0cyclopropyl-19-nor-3a,5a-cyc1oandrostane-6/3,l7,B-diol 6,17-diphenylpropionate (4) 17a-methyl-7-spirocyclopropyl-3a,5u-cycloandrostane-6fi,17 8-diol 6,17-isova1erate (VIII), etc.

EXAMPLE l8 Following the procedure of the paragraph appearing after Example 16 but substituting 7-spirocyclopropyl-3a, 5a-cycloandrostane-6fl,17fi-diol 17-acetate 3-p-toluenesulfonate as starting material yields 7-spirocyclopropyl- 3a,5a-cycloandr0stane-6/3,17,8-diol 17-acetate (VIII). In like manner, substituting 7-spirocyclopropyl-l9-nor-3a, 5a-cycloandrostane-6fl,17fi-diol 17-acetate 3-p-toluenesulfonate as starting material, yields 7-spirocyclopropyl-19- nor-3a,5a-cycloandrostane-6fi,17B-diol 17-acetate (VIII).

EXAMPLE 19 A solution of 2.5 g. of 7-spirocyclopropyl-5-androstene- 35,17fl-diol 17-acetate (IX) (obtained as in Example 13) in 26.65 ml. of cyclohexanone and 40 ml. of toluene is distilled to remove traces of water, then 0.83 g. of aluminum isopropoxide is added to the mixture. The reaction mixture is refluxed for about L75 hours, cooled and poured into iced 2 N hydrochloric acid solution. The organic phase is washed, dried and chromatographed through (1 7-spirocyclopropyl-l9-nor-5-androstene-3B,175-diol 17-propionate (IX),

(2) 17a-methyl-7-spirocyclopropyl-5-androstene-3fi,17B-

diol l7-valerate (IX),

(3) 17 x( l-propynyl)-7-spirocyclopropyl-l9-nor-5- androstene-3B,17fl-diol l7-acetate (IX),

(4) 17a 2-butenyl -7-spirocyclopropyl-5-androstene 35,17/3-diol 17-trirnethylacetate (IX),

(5) 3B-hydroxy-7-spirocyclopropyl-19-nor-5-androsten- 17-one (IX), etc.,

yields, respectively,

( 1 17/3-hydroxy-7-spirocyclopropyl-19-nor-4-androsten- 3-one 17-pr0pionatc (X),

(2) 17fl-hydroxy-l7a-methyl-7-spirocyclopropyl-4- androsten-3-one 17-propionate (X),

(3) l7fi-hydroxy- 1 70a l-propynyl -7-spirocyclopropyll9-nor-4-androsten3-one 17-acetate (X),

(4) 17,8-hydroxy-17a(2-butenyl)-7-spirocyclopropyl-4- androsten-Ia-one l7-trimethylacetate (X),

(5) 7-spirocyclopropyll9-nor-4-androstene-3,17-dione (X), etc.

EXAMPLE 20 1 7fl-hya'roxy-7-spir0cycl0pr0pyl-4-andr0sten-3-one (X) A solution containing 0.6 g. of 175-hydroxy-7-spiro cyclopropyl-4-androsten-3-one 17-acetate (X) (obtained in Example 19) and 2.5 g. of potassium carbonate in ml. of water and 40 ml. of methanol is heated at reflux for about 0.5 hour. The solution is cooled and the precipitated product filtered, washed with water, dried, chromatographed through a column of Florisil and the product recrystallized from acetone-Skellysolve B to yield 0.4 g. of 17/3-hydroxy-7-spirocyclopropyl-4-androsten-3- one (X) melting at 198 to 199 C., alc. max. 24l m e=16,400. The infrared absorption and NMR spectra support the stucture proposed for the product.

Analysis.Calcd. for C H O (percent): C, 80.21; H, 9.62. Found (percent): C, 79.76; H, 9.69.

Following the procedure of Example 20 but substituting other 17-acylates of Formula IX, such as (1 17,8-hydroxy-7-spirocyclopropyl-19-nor-4-androsten- 3-0ne l7-butyrate (X),

(2) 17fi-hydroxy-17a-methyl-7-spirocyclopr0pyl-4- androsten-3-one 17-propiolate (X),

(3) 17fl-hydroxy-17ot-ethynyl-7-spirocyclopropyl-l9- nor-4-androsten-3-one l7-phenylpropionate (X),

(4) 17fl-hydroxy-17a-vinyl-7-spirocyclopropyl-4- androsten-3-one 17-decylenate (X), etc.,

yields, respectively,

( 1 17 3-hydroxy-7-spirocyclopropan-19-nor-4-androsten- 3-one (X),

(2) 17,8-hydroxy-17a-methyl-7-spirocyclopropyl-4 androsten-3-one (X),

(3) 17 B-hydroxy-17a-ethynyl-7-spirocyclopropyl-19- nor-4-androsten-3-one (X),

(4) 17/3-hydroxy-17ot-vinyl-7-spirocyclopropyl-4- androsten-3one (X), etc.

EXAMPLE 21 17B-hydroxy-7-spir0cycl0pr0pyl-5li-afldrostan-3-0ne (XI) A solution of l g. of 17;?-hydroxy7-spirocyclopropyl-4- androsten-B-one (X) (obtained as in Example 20) in 250 ml. of ethyl alcohol is reacted with hydrogen using 5% palladium on charcoal catalyst until 1 mole quivalent of hydrogen is absorbed. The catalyst is removed by filtration through a bed of Celite (diatomaceous earth). The filtrate is concentrated to dryness, and the residue chromatographed and recrystallized from a mixture of acetone and Skellysolve B to give l7fl-hydroxy-7-spirocyclopropyl-5fi-androstan-ol-3-one (X).

Following the procedure of Example 21 but substituting as starting materials representative compounds of Formula X, such as 1) 17 fl-hydroxyJ-sp-irocyclopropyl-19-nor-4-androsten- 3-one-17-acetate (X),

(2) 17,8-hydroxy-17at-propyl-7-spirocyclopropyl-4- androsten-3-0ne (X),

(3) 17fi-hydroxy-7-spirocyclopropyl-19-nor-4-androsten- 3-one 17-propionate (X), etc.

yields, respectively,

( 1) 17p-hydroxy-7-spirocyclopropyl-19-nor-5/3- androstan-3-one l7-acetate (XI),

(2) 17,6-hydroxy-17a-propyl-7-spirocyclopropyl-5B- androstan-3-one (XI),

(3) 17,8-hydroxy-7-spirocyclopropyl-19-nor-5B- androstan-S-one 17-propionate (XI), etc.

To a solution of 1 g. of 7-spirocyclopropyl-5fl-androstane-3,17-dione (XI) (prepared as in Example 21) in 10 ml. of boiling methanol, 2 ml. of pyrrolidine is added. The resulting solution is heated briefly under nitrogen, concentrated and allowed to cool. The crystalline solid that separates is isolated by filtration, washed with a small volume of methanol and dried to give 7-spirocycl0propyl- 5fl-androstane-3,17-dione 3-pyrrolidinyl enamine in the form of a crystalline solid.

A volume of 10 ml. of a 20% by Weight suspension of sodium acetylide in xylene is centrifuged and the solid that separates is taken up in 60 ml. of redistilled dimethyl sulfoxide. To the resulting mixture of 5 g. of 7-spirocyclopropyl-5,8-androstane-3,17-dio'ne 3-pyrrolidinyl enamine is added. The mixture is maintained under an atmosphere of nitrogen for about 5 hours, and the excess of sodium acetylide destroyed by the dropwise addition of water. About 20 ml. of Water and 50 ml. of methanol is added to obtain a clear solution which is then heated on a steam bath for about 1 hour. This material is extracted with ether and the ethereal extract washed successively with dilute hydrochloric acid, dilute sodium carbonate solution, and Water, then dried over anhydrous magnesium sulfate. The dried solution is filtered and the filtrate evaporated to dryness. The residue is triturated with a mixture of ether and Skellysolve B and recrystallized twice from a mixture of acetone and Skellysolve B to give pure 17fi-hydroxy-17tz-ethynyl-7-spirocyclopropyl- 5 ,B-androstan-3-one (XI Following the procedure of Example 22 but substituting 7 spirocyclopropyl-19nor-5fl-andr0stane-3,17-dione (XI) as starting material, yields 17fl-hydroxy-l7a-ethyny1- 7-spirocyclopropyl-19-nor-5/3-androstan-3-one (XI).

Following the procedure of the immediatey preceding paragraph and of Example 22 but substituting the following acetylide:

(1) sodium methylacetylide,

(2) lithium acetylide,

(3) sodium trifluoromethylacetylide, etc.,

yields, respectively,

5,8-anclrostan-3-one (XI),

androstan-3-one (XI,

(3) 17fi-hydroxy-17ot-trifluromethylethynyl-7-spirocyclopropyl-5fi-androstan-3-one (XI), etc. and the 19-nor counterparts (XI) of the foregoing.

EXAMPLE 23 1 7 fi-hydroxy-I 7 a-ethyl-7-spir0cycl0pr0py [-5 5- androstan-S-one (XI) A catalyst Comprising a suspension of 0.1 g. of 1% palladium on charcoal in 30 ml. of dioXane (purified by passage through a column of neutral alumina) is reduced at atmospheric pressure with hydrogen. A solution of 0.4 g. of 17,8-hydr xy-17ot-ethynyl-7-spirocyclopropyl-SB-androstan-3-one (XI) (obtained as in Example 22) in 5 ml. of dioXane is injected into the reaction flask through a rubber stopper. Hydrogenation is continued until 2 moles are consumed at atmospheric pressurenThe catalyst is removed by filtration and the filtrate concentrated on a rotary evaporator. The oily residue is chromatographed through a column of 65 g. of Florisil. The eluted material is crystallized from aqueous methanol. Recrystallization from the same solvent gives I'Ifl-hYiifOXY-l7ct-SPIIO- cyclopropyl-SB-androstan-3-one (XI).

Following the procedure of Example 23 but substituting other compounds of Formula XI for the starting material employed therein, such as (1) 17,B-hydroXy-17a( l-propynyl -7-spirocyclopropyl- 19-nor-5fi-androstane-3-one (XI),

(2) l7fl-hydroxy-l7a-trifiuoromethylethynyl-7-spirocycloproyyl-Sfl-androstan-3-one (XI), etc.

yields, respectively,

( 1) 17,8-hydroxy-17ot-propyl-7-spirocyclopropyl-19-nor- 5/3-androstan-3-one (XI),

(2) 17,8-hydrxy-17a(3,3',3'-trifluoropropyl)-7-spirocyclopropyl-fi-androstan-3-one (XI), etc.

EXAMPLE 24 7-spirocyclopropan-5/3-andr0stan-I 7u-ethenyl-I 7/3-01- 3-0ne (XI Following the procedure of Exampe 23 but permitting the hydrogenation described therein to proceed until only 1 mole of hydrogen is consumed instead of 2 moles, yields of 1713 hydroXy-17ot-vinyl-7-spirocyclopropyl-5{3- androstan-3-one (XI).

Following the procedure of Example 24 but substituting the following compounds for the starting material employed therein, such as 1) 17,8-hydroxy-17a-ethynyl-7-spirocyc1opropyl-19-nor- 5,9-androstan-3-one (XI (2) 17fi-hydroXy-17ct( l-propynyl)-7-spirocyclopropyl- 5,8-androstane-3-one (XI),

(3 17,8-hydroxy- 17u( l-butynyl -7-spirocyclopropyl-19- nor-5fl-androstan-3-one (XI),

(4) 17fl-hydroxy-l7a-trifluoroethylethynyl)-7-spirocyclopropyl-5B-androstane-3-one (XI) etc.

yields, respectively,

(1) 17B-hydroxy-17ix-vinyl-7-spirocyclopropyl-19-nor- 5,8-androstan-3-one (XI),

( 2) 17 p-hydroxy- 17a l-propenyl -7-spirocyclopropyl- Sfl-androstan-B-one (XI),

(3) 17fl-hydroXy-17a( 1-butenyl-7-spirocyclopropyl)-5{3- androstan-3-one (XI),

(4) 17,8-hydroxy-17a-trifiuoromethylvinyl-7-spirocyclopropyl-SB-androstan-3-one (XI), etc.

EXAMPLE I 7 3-hydr0xy-1 7 oc-ethynyl-7 -spir0cycl0propyl-5 flandr0stan-3-0ne 1 7-acetate (XI) A solution of 1 g. of 17B-hydroxy-17u-ethynyl-7-spirocyclopropyl-SB-androstan-3-one (XI) (prepared as in EX- ample 22), in 5 ml. of pyridine and 2 ml. of acetic anhydride is heated under nitrogen at 80 C. for about 16 hours. The solvent is removed on a rotary evaporator and 40 the residue triturated with Skellysolve B, then washed with Skellysolve B and methanol, and crystallized from acetone-Skellysolve B to give 17,8-hydroxy-17x-ethynyl-7- spirocyclopropyl-Sfl-androStan-3-one 17-acetate (XI).

In the same manner as in Example 25, the 17-butyrate, 17-hexanoate, 17-phenylacetate, 17-cinnamate and other like 17-esters of 17,8-hydroxy-17ot-ethynyl-7-spirocyclopropyl-SB-androstan-E)-one (X1) are prepared by reaction of the 17B-alcohol (XI) with the appropriate acid anhydride or halide.

Following the procedure of the immediately preceding paragraph and of Example 25, but substituting other starting materials, such as 17p-hydroXy-17a-(1-propynyl)-7- spirocyclopropyl-19-nor-5,8-androstan-3-one (XI), 17fl-hydroxy-l7a-ethyl-7-spirocyclopropyl-S S-androstan-3 one (XI), 17fi-hydroxy-17tx-isopentyl-7-spirocyclopropyl 19- nor-5p-androstan-3-one (XI), 17fi-hydroxy 17a (2- butenyl)-7-spirocyclopropyl-Sfl-androstan 3 one (XI), etc., yields the corresponding 17-acylate.

EXAMPLE 26- 7 6-12 1droxy-7-spirocyclopropyl-5a-andr0stan-3-0ne (XIII To 200 ml. of liquid ammonia, 0.15 g. of lithium wire cut in small pieces is added. After the lithium dissolved, 2 g. of 17fl-hydroXy-7-spirocyclopropyl-4-androsten-3 one (X) (obtained as in Example 20) in 40 ml. of tetrahydrofuran (purified by passage through a column of aluminum oxide) is slowly added to the solution of lithium in ammonia at reflux. The resulting solution is allowed to stand for about 15 minutes, then 3 g. of solid ammonium chloride is added and the ammonia is rapidly evaporated on a steam bath. Water is added and the product extracted with ether. The ether extract is washed successively with water, dilute hydrochloric acid, water and brine, then dried over magnesium sulfate, filtered and concentrated to dryness. The amorphous solid is dissolved in methylene chloride and the solution poured onto a column of Florisil. Following chromatography and crystallization from ethyl acetate, the product (XIII) is obtained. Recrystallization from acetone gives pure 17B-hydroXy-7-spirocyclopropyl-5aandrostan-3-one (XIII).

Following the procedure of Example 26 but substituting other compounds of Formula X, such as 1) 17fl-hydroXy-7-spirocyc1opropyl-19-nor-4-androsten 3-one (X),

(2) 17,6-hydroxy-17zit-methyl-7-spirocyclopropyl-4- androsten-3-one (X), etc.,

yields, respectively,

(1) 17 ,6-hydr0Xy-7-spirocyclopropyl-19-nor-5 a-androstan- 3-0ne (XIII),

(2) 17fi-hydroXy-17a-methyl-7-spirocyclopropyl-Sotandrostan-3-one (XIII), etc.

EXAMPLE 27 7-spir0cycl0propyl-5ot-androstane-3,1 7-di0ne (XIII) To a solution of 0.3 g. of 17fi-hydroXy-7-spirocyclopropyl-Sa-androstan-S-one (XIII) (obtained as in Example 26) in 10 ml. of acetone, 0.25 ml. of 8 N chromium trioXide reagent (J. Org. Chem. 21 1547) is added with cooling. The crude product (XII) is precipitated with water, filtered, dried and recrystallized from acetone- Skellysolve B to give 7-spirocyclopropyl-Sot-androstane-3, 17-dione (XIII).

Following the procedure of Example 27 but substituting -hydroxy-7-spirocyclopropy1-19-nor-5a-androstan 3- one (XIII), yields 7-spirocyclopropyl-19-nor-5w-androstane-3,17-dione (XIII).

EXAMPLE 28 I 7,8-l1ydr0xy-I 7 a-ethynyl-7-spir0cycl0pr0pyl-5 :xandrostan-3-0ne I7-acerate (XIII) Following the procedure of Example 22 but substituting 7-spirocyclopropyl-5a-androstane-3,17-dione (XIII) (pre- 

